well, i actually started on cake walk, just to get a sense of how things work w/o worrying about the AI players.
moved right up to normal for a game, then tough.
now i play crippling or maso. i usually play abund/common/uncommon for the star and planet settings, tight or loose clusters, abundant anomolies, and research usually on very slow. usually play with 9 or 7 opponents. i only play with blind exploration if i use loose clusters; otherwise, it's too likely that 1 player ends up in the corner with only 3 planets.
crippling gives me the best challenge i can still reliably beat. sometimes in maso i'm playing games with a strong disadvantage. sometimes i like that, sometimes it's kind of fun to give it my best and still lose. above maso i have increasing difficulty. i can still win, but it usually is only through tactics i don't totally like (selling opponents ships that make them weaker against you, stationing ships next to mining bases and then giving the ships to the base's owner's opponent so that the base is destroyed. those are good ways to win, but i prefer having fun and have more fun when i feel immersed.
lately i've been playing mods more than anything. i took the example mod and removed the new races, new UI, and slimmed down tech tree. i added a couple new techs (most notably a line of medical techs that boost pop growth) and other things. also tried to 'help out' some of the typically weaker players (i don't think i've played any un-modded games where the iconians were a significant threat).
your miliage and preferences may vary, or course. if you want to try and go to a higher difficulty level, a good thing to do is give yourself some 'training wheels' by modding in some nice bonuses for your race of choice.