Many drug fragments and therapeutic compounds contain multiple pyridines and diazines. Developing site-selective reactions where specific C-H bonds can be transformed in polyazine structures would enable rapid access to valuable derivatives. We present a study that addresses this challenge by selectively installing a phosphonium ion as a versatile functional handle. Inherent factors that control site-selectivity are described along with mechanistically driven approaches for site-selective switching, where the C-+PPh3 group can be predictably installed at other positions in the polyazine system. Simple protocols, readily available reagents, and application to complex drug-like molecules make this approach appealing to medicinal chemists.