I've heard Cthulhu+Dagon+Hydra is the hardest. Is that true?

Hastur and Tulzscha work pretty well together. Unfortunately, they don't really have any synergy for the final battle like Cthulhu has with Hydra and Dagon. Plus, it's the only official instance in which two heralds are allowed at once, so yeah, I'd say that'd make that trio the top dog.

Yep, for final battle Cthulhu + Dad & Mom makes it probably one of the craziest to beat, though most Innsmouth AO are crazy enough anyway.

For more interesting combos, try Rhan-Tegoth with the Tattered King or Father Dagon. If your draw is sucky enough (Cultist + Child of Goat + Dark Druid), you can see our dear King pasting posters all over town, driving citizens fanatical with love, in the former case. In the latter case... you'll probably never have enough information to seal a gate, not to mention that doomers would flow like water.

Hm, just thought of something amusing. Yibb-Tstll + Tattered King. Sure, nothing would up the Terror too quickly, but if you draw Oliver Thomas... you better hope Patrice is in the game, or else you could look forward to facing the all-seeing Miss Sauron in final battle. In that case, imagine Prof Rice joining you. Exciting, no?

I disagree that Cthulhu+pals is the hardest. I think that overall, Alatch-Natcha is still queen (or king? is it male or female?) of the Ancient Ones, difficuly-wise. No other AO has such game-breaking power. Sure, its attack isn't the strongest, but it's still nothing to sneeze at and still ranks up pretty high not to mention the defenses. So pair Alatch-Natcha even with nothing and I still call it harder than any combination. Ofcours, you can always add something like Black Goat to make him/her something to be even more afraid of.