Small molecule mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia–reperfusion injury, and neurodegenerative diseases. This communication will review the small molecule mitochondrial uncouplers reported to date and explore their potential as therapeutics.