The biggest change in D&D (IMO) over the years was the d20 shift to 3E. In many ways, it really became a different game and personally I wish they had called it something else. But, I understand the importance of brand names, so I get why they stuck with D&D...
From what I understand, 4E went too far in overcomplicating things, and so 5E went too far back in over simplifying things, and hopefully 6E will swing the pendulum back the other way, but slow it down.
Another big change when 3E came along as in the spirit of the game. 3E felt completely different to me than AD&D and prior editions. I don't get that sort of difference in feel between 3E and 5E, for instance.