This review documents the changing perspectives on the function of fatty-acid synthase and fatty-acid synthesis in human tumor biology. With the recent discovery that human cancer cells express high levels of fatty-acid synthase and undergo significant endogenous fatty-acid synthesis, our understanding of the role of fatty acids in tumor biology is expanding. Once considered largely an anabolic-energy-storage pathway, fatty-acid synthesis is now associated with clinically aggressive tumor behavior and tumor-cell growth and survival and has become a novel target pathway for chemotherapy development. These findings will ultimately enhance our understanding of fatty acids in tumor biology and may provide new diagnostic and therapeutic moieties for patient care.