Insulin-sensitizing thiazolidinediones (TZDs) correct a root cause of type 2 diabetes and potentially other diseases of metabolic dysfunction, including conditions ranging from oncologic, inflammatory, and neurodegenerative diseases. Importantly, compounds with this mode of action can modify disease progression, as opposed to simply mitigating symptoms. However, side effects have limited the use of marketed agents. Moreover, the same and additional issues have prevented development of newer agents, and no new compounds with this mode of action have been approved since 1999. Here we briefly review the drug discovery track record of compounds in the TZD class as well as several classes of compounds that have been designed with substitutes for the TZD ring, while maintaining and/or expanding the ability to directly activate peroxisome proliferator-activated receptor (PPAR) transcription factors. A key discovery that could change the course of drug discovery in this area is a newly identified mitochondrial target for the insulin sensitizers. This has allowed new drug discovery into molecules designed to maintain this mitochondrial interaction while specifically avoiding significant interactions with PPAR receptors. This commentary suggests that a fresh approach could pave the way for a new directed group of therapeutic agents with potential for disease modification of common metabolic disorders.