The one big (huge in some people's minds) change is the damage save.
You don't track hit points. You don't roll damage. Everybody has a damage save and when damage is done, you roll a new save - the toughness save. Depending on how you do at that, you may shrug it off as a minor scrape or bruise, or you may fail badly all the way up to death being a result.
Some people will hate this. Some will love it. Personally, I find that it is a great option depending on the type of games you want to run. D&D does a good job abstracting your damage. But it comes at a cost. If you want to have the game where the protagonists are being slowly worn down and becoming a little less effective because of that, then D&D is not a very good fit. Until you transition from 1HP to 0 HP, you don't even suffer a consequence for taking damage. Then you move from 0HP to -1 through -9 where you are out and bleeding to death. Then you die.
True20 doesn't play like that. You will get less effective over time if you keep getting injured.
Did I mention that you don't roll damage? Weapons have a damage amount, the variable results from the 1 toughness save rolled.
A design decision in True20 was to keep the die rolls to a minimum. If you are looking to have each PC roll a minimum of dice in any given round, True20 does that well! No iterative attacks, no handfulls of d6's when a powerful spell goes off. Minimal die rolls.
No alignment - characters have virtues and vices, and these directly tie into conviction. Think of conviction as action points and you are good. Characters spend conviction to do things and they recover conviction over time - or by playing up virtues and vices. A character might be brave and greedy. Give the character a chance to shield a bunch of innocents in a gun battle with his own body and maybe he will reinforce his bravery virtue. Give him a chance to snag that pile of 100's that the bank robbers dropped on the street as they ran, and maybe he will reinforce his greedy vice. Either way, he will gain conviction points.
Conviction allows you to do a lot of the same things action points do, but each of the three core classes has a special ability that they can tap with conviction. Like a warrior might shake off minor damage effects during a battle by spending conviction. Non-warriors cannot do that! Think your action movies where the protagonist is getting beaten up. He is getting sluggish, weak and the bad guy is taunting him. The bad guy says one thing too much and then the hero finds his resolve and comes back almost like those bruises and cuts are no longer affecting him. In True20 terms, the warrior just blew a conviction point to set aside the effects of those blows.
It can be very cool once the players get a hang of it!
There are only 3 core classes. Adept, Expert and Warrior. Adepts are your spellcasters, depending on genre. It doesn't have to be magic, it can be technology, or whatever. Experts are the skill monkeys. Warrior are, well, warriors. Classes don't have class abilities (aside from the conviction ability). Characters get feats every level and they buy the class abilities they want. There is a long list of general feats, and shorter lists of Adept/Expert/Warrior feats. Furthermore, Adepts can use a feat to buy a power.
Powers work by inducing fatigue. So, a powerful adept needs to make fatigue saves when using powers. Failure means the power made the character a little more tired.
Powers scale in completely different ways than D&D spells! With a strong save, you can use weak powers all day long. With a strong save, luck, and conviction, you can use a lot of powerful powers. But with bad luck, you might not get more than one or two off.
Still, with conviction, there are a lot of options in the player's hands.
Stats are recorded based on the bonus you are granted. So, a character's stats might look like this:
Str: +1, Dex: +2, Con: 0, Int: +2, Wis: 0, Cha: +1
For the melee favoring characters, they might be displeased with the fact Strength doesn't make it easier to hit opponents. It makes it easier to hurt opponents, by increasing the toughness save, but not easier to hit. Dexterity affects your ability to hit, whether in melee or at range.
One thing, it is possible for a character to max out Con to max out the toughness save. This can make it very difficult for the GM to hurt that character without increasing the risks to other characters. If a player goes that route, I tend to encourage their toughness as their schtick. Let them be tough! But emphasize the strengths of the other characters as often as possible. A con maxed warrior can look dominating and if you think the primary challenge is how to hurt the character, you run the risk of wiping everybody else out. Let the character be tough and throw fights at him where he is practically unstoppable. Let skills and powers resolve all the other problems. Then the character feels the lack of non-combat resolutions, but gets to be tough.
I once made the mistake of trying to challenge the tough character with a combat challenge that would make him fearful. The other characters went down too quickly, the tough character eventually prevailed, but couldn't resolve anything else until the other characters were back up. It was my bad call and I learned from it, so I pass it along as cautionary advice.
Initially I worried a lot about new monster design, but I found the dynamics of the system made it much easier. After a few trial runs, you get pretty good at it. I also found it even quicker and easier to rebrand monsters with a new description and old stats and the players never noticed that they ended up fighting the same monster three times with one feat swapped out and a new coat of paint.
Once the mechanics get lighter, the players seemed to lighten up as well.
I am glossing over a lot of things. But I am sure other folks will join in.
If you are not PDF adverse, get a PDF of True20. It is less expensive and will allow you a chance to look through the system. The revised version has just recently come out. I haven't picked it up yet, though I am meaning too. The revised version dumps the sample settings and inserts the companion book content. The companion discusses genres and how you might implement them. So depending on whether you want a few sample settings, or if you want more of the toolkit, choose the non-revised book, or the revised book.