Free radical-catalyzed cis-trans isomerization of unsaturated lipids and its outcome in biomimetic conditions are reviewed. They provided indications for an endogenous origin of trans unsaturated fatty acids in humans by the attack of thiyl radicals. A multidisciplinary approach highlights the relevance of this topic. The role of cis lipid geometry and its maintenance in the biological environment is an emerging question, with future developments in the fields of lipidomics, biology, and medicine.