I'm gonna have to side with Lisa on this; Rocko's Modern Life trumps Spongebob Squarepants (even if my choice is out of pure nostalgia for the show)! I'll admit, I did watch Spongbob when it was red hot (I was just starting 9th grade) and I even liked some of the earlier episodes and seasons, but now I do believe it's time for Spongebob to be put out to pasture. The last full episode I watched in its entirety wasn't that good. Also, right around when I was in high school, I started watching more of Cartoon Network's programming (namely Toonami and Adult Swim for the anime since I was just starting getting into that form of animation) as the then-current lineup on Nickelodeon was more for the younger crowd.
For me, I think the last true Nicktoon was Invader Zim. Zim captured what the 90s Nicktoon had: those programs where not only entertaining, but they offered stuff that both younger and older viewers could enjoy. With that said, I seriously would pick Invader Zim to be one of the best Nicktoons, along with classic Ren and Stimpy and classic Rugrats. And since Lisa mentioned this show, The Adventures of Pete and Pete is by far the best live action Nick show the network has ever aired! I love that show so much that I even have the out of print box sets and pull them out on occasion and watch them.