Desaturation (O 2-dependent dehydrogenation) of long chain fatty acyl derivatives is a ubiquitous biotransformation which generates a wide variety of oxidized lipidic natural products with important biological properties. Recent advances in molecular/structural biology coupled with the application of novel mechanistic probes have led to a more sophisticated understanding of how fatty acid desaturases function. In this review, the major milestones along the pathway of desaturase research will be highlighted from a bioorganic perspective. 178 references are cited.