p97 is a homohexameric, toroidal machine that harnesses the energy of ATP binding and hydrolysis to effect structural reorganization of a diverse and primarily uncharacterized set of substrate proteins. This action has been linked to endoplasmic reticulum associated degradation (ERAD), homotypic membrane fusion, transcription factor control, cell cycle progression, DNA repair, and post-mitotic spindle disassembly. Exactly how these diverse processes use p97 is not fully understood, but it is clear that binding sites, primarily on the N- and C-domains of p97, facilitate this diversity by coordinating a growing collection of cofactors. These cofactors act at the levels of mechanism, sub-cellular localization, and substrate modification. Another unifying theme is the use of ubiquitylation. Both p97 and many of the associated cofactors have demonstrable ubiquitin-binding competence. The present review will discuss some of the current mechanistic studies and controversies and how these relate to cofactors as well as discussing potential therapeutic targeting of p97.