Toughest leagues (or their functional equivalents) that I can think of for boys (not necessarily in order):
Greater Spokane League WA: North Central, Joel Ferris, Mead, Central Valley, Lewis & Clark, University, Mt. Spokane, Shadle Park, Gonzaga Prep, Rogers.
10 schools, 4 of which have made it to NXN while another (CV) probably should have in 2006, and 3 of them have finished a season US#2 or better at some point; University has been NW Top-5, Mt. Spokane has been near the NW Top-10, and Shadle Park and Gonzaga Prep has had some good individuals (in the last two years: Nathan Weitz, Connor McCandless both ~9:00 or better) and some years have state-caliber teams as well.
Sunset League CA: Dana Hills, Trabuco Hills, El Toro, San Clemente, Mission Viejo, Capistrano Valley.
6 schools, 3 of which have made it to NXN though haven't yet had a top-5 finish (Dana Hills has been sixth though, and Trabuco Hills ninth).
Region IV UT: American Fork, Herriman, Lone Peak, Pleasant Grove, Riverton, Lehi
American Fork is the only school to make it to NXN, though Herriman was very close to making it last year (IMO they would have been an At-Large invite if their #4 was just 15 seconds faster at NXN-SW). Very deep group though, with all the boys teams except Lehi getting ranked at some point in the last three or four years (I think I had PG ranked for at least part of one year? could be remembering wrong though).
Lake Conference MN: Wayzata, Eden Prairie, Edina, Hopkins, Minnetonka
Three of the five have made it to NXN, while the others have all had some good individuals if not regionally strong teams.
I'm sure there are others, but I didn't really look too far. The above is for boys only, of course...