The 2001 Nobel Prize in Medicine, awarded to two yeast researchers for contributions to understanding the eukaryotic cell cycle, spotlighted yeast as an experimental model system in biomedical research. Major discoveries of molecular processes underlying lipid and biomembrane biogenesis were first made in yeast: secretory pathways, vesicle and membrane fusion, and the unfolded protein response. The discovery of programmed cell death that is conserved at multiple levels (quite intriguing for a unicellular organism), and energy metabolism controlled by adenosine monophosphate-activated protein kinases, mitogen-activated protein kinase signaling pathways, and the target of rapamycin (TOR) pathway (originally discovered in yeast)-all refer to functional and structural similarities with mammalian cells beyond the mere metabolic level. This article reviews recently uncovered aspects of fatty acid-associated malfunctions and lipotoxicity in yeast that may aid in understanding the molecular basis of lipid-associated disorders in mammals.