Lipid droplets (LDs) are found throughout all phyla across the tree of life. Originating as pure energy stores in the most basic organisms, LDs have evolved to fill various roles as regulators of lipid metabolism, signaling, and trafficking. LDs have been noted in cancer cells and have shown to increase tumor aggressiveness and chemotherapy resistance. A certain transitory state of cancer cell, the polyaneuploid cancer cell (PACC), appears to have higher LD levels than the cancer cell from which they are derived. PACCs are postulated to be the mediators of metastasis and resistance in many different cancers. Utilizing the evolutionarily conserved roles of LDs to protect from cellular lipotoxicity allows PACCs to survive otherwise lethal stressors. By better understanding how LDs have evolved throughout different phyla we will identify opportunities to target LDs in PACCs to increase therapeutic efficiency in cancer cells.