Personally I found Twilight fairly easy when I played on tough with a custom-made race geared towards economic, research, and morale bonuses, Super Diplomacy, and tech trading and brokering on. I traded amongst my neighbors to get all the techs that grant any bonuses, and built up a superpower pretty quickly.
I felt that I wasn't really feeling the uniqueness of the Twilight tech trees by easily benefiting from the best of them all, so I deleted my custom race, turned off tech trading and brokering, and played as a standard race without modifying it. That made the game a helluvalot harder. I play pretty peacefully, and thus my research of weaponry doesn't come so quickly. As such I've struggled to stay alive in recent games, still on tough.
At the same time, I have had to tinker with other settings. I don't like it when AIs surrender. In my most recent experiences with that setting turned on (about 6 months ago) civs surrendered way too easily. This led to an immense galaxy with 5 or 6 races instead of 10, 1 of which was suddenly extra-powerful. I didn't particularly enjoy that. I think I need to turn off the ascension victory too, because it seems to happen quicker than I'd like.
Apart from that, perhaps if I adopted a more warlike strategy the game would suddenly get easier for me. The same holds true for Civ 4 I think, except that Civ 4 with no AI bonuses is not a challenge no matter what strategy I take. Gal Civ 2 with no AI bonuses is a challenge for my more peaceful approach to the game.