Recent advances have significantly increased our understanding of how sterol regulatory element binding proteins (SREBPs) are regulated at the transcriptional and post-transcriptional levels in response to cellular signaling. The phosphatidyl inositol-3-kinase (PI3K) and SREBP pathways intersect at multiple points, and recent insights demonstrate the importance of tight regulation of the PI3K pathway for regulating SREBPs in the adaptation to fluctuating dietary calorie load in the mammalian liver. In addition, genetic and genome-wide approaches highlight new functions for SREBPs in connecting lipid metabolism with other cellular processes where lipid pathway flux affects physiologic or pathophysiologic adaptation, such as cancer, steatosis, and innate immunity. This review focuses on recent advances and new roles for mammalian SREBPs in physiology and metabolism.