I played on Huge with rare/rare/rare stars/planets/habitable, five opponents (Drengin, Arcean, Yor, Torean, Altarian for that classic feel) and had the most fun I've ever had in the game. Part of it was that I had incredible luck with bonus tiles - one planet had two 700% research tiles, and another planet had one 300% and one 700% manufacturing tile. The first planet effectively catapulted me into a permanent research lead.
The other thing I did was accidentally leave it on 8 minor races, which provided 8 additional worlds that I could colonize with extreme prejudice if need be, and both the Vegans and Dread Lords arrived later. I ended up going for an alliance victory after the Arceans got their stupid "They touched the Telenanth and will become gods" event, because declaring war on them meant every other civilization declared war on me, which cut my trade income to nothing. I should have used my awesome diplomacy to keep everyone at each other's throats, though.
I did wipe out the Drengin, sort of. I had transports right on top of their worlds when they decided to surrender to me. I was on the verge of wiping out the Yor when the Arcean event happened.
What I noticed: Having an awesome research world did as I noted above. Having an awesome industry world meant I could build some fairly expensive ships fairly quickly. The other races were much more limited in what they could accomplish due to a lack of that much luck in early colonization. The minors were a huge resource in terms of everything from tech trading to expansion. Life support and starbases were very important for enabling me to get anywhere.
I'd do it again, although the early colony grab is really frustrating.
Also, difficulty was set at normal with randomized intelligence. I need to move up to the next level, I think.