I'm gonna go out on a limb and claim
SimCity 4 as the best in the title. It was the first game in which I actually managed to turn a profit, thanks in large part to the UI and its extensive data projections. (Maybe I'm just not cut out for city planning.

) Transportation infrastructure was greatly expanded from the older games, and driving about the city in
Rush Hour was just plain fun. It was the first game I
played rather than planned.
Star Control II was the best sequel ever
THIS THIS A THOUSAND TIMES THIS
And I never played far enough into SC3 to deem it good or bad.
3 is far superior to 2. The economic simulation in 3 is the best and most sophisticated of any game I've ever played and quite possibly the best in any game billed for mainstream audiences (i.e. not an economic simulation game designed solely for business students)
Amen. RT2 was already solid, and probably my most-played game to date after Civ2. RT3 took that model and improved it in just about every way.
Speaking of Civ2, I still consider it the pinnacle of the series. It's clean, straightforward, and scriptable, and ToT added whole new dimensions (literally!). 3 and 4 built on different elements of the formula to the exclusion of others but neither carried the whole package forward.
Alpha Centauri probably came closest, but it was more a spin-off than a sequel and comparatively handicapped in third-party modding (that, and its tech pacing was horrendously top-heavy).