At high levels, it is very difficult to meaningfully threaten the PCs. Even if you disintegrate one of them, the party will have access to wish spells, divine intervention, and other ways to recover. Hopefully, by this point in the campaign, you have made each of them care about something - perhaps a character is a lord, and has a castle. Perhaps he is married. Maybe he's taken on an apprentice, who has by the highest tier gone on to become an adventurer. These are weaknesses you can exploit, because even a nearly invulnerable PC can't be everywhere and protect everything. Sure, you have a clone to fall back on, but how well is your tower full of stuff and people protected? A character in the epic tier of play isn't just a person, he's an organization of henchmen, hirelings, businesses, etc. They're all vulnerable.
An ancient dragon is too clever to face a high level party, so if they aren't very subtle about going after the wyrm they'll get to the lair only to find most of the hoard removed (perhaps the last group of kobolds is heading for the tunnels when the party arrives) and the dragon nowhere to be found. When they get back to town, it is a smoking ruin--the fields are despoiled, the livestock are eaten, and the few surviving townsfolk blame the adventurers for bringing the dragon's wrath upon them.
For an example of high level adventure, check out the Bloodstone Pass series. It's made to work with the Battlesystem rules for the 2nd edition, but you can easily find streamlines rules for handling the warfare elements. The PCs face a variety of challenges from diplomacy to fighting epic bad guys, but the core concept of the three adventures is that the party isn't just a band of adventurers any more--they have something to fight for, and potentially lose, because they're the leaders of the barony.