The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3? is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3? -knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3? overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3? isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3? depletion promotes autophagy-dependent degradation of C/EBP-d, preventing induction of the master adipogenic factors, Ppar? and C/EBP-a. Transcriptomic data indicate that 14-3-3? acts upstream of hedgehog signalling-dependent upregulation of Cdkn1b/ p27Kip1. Indeed, concomitant knockdown of p27Kip1 or Gli3 rescues the early block in adipogenesis induced by 14-3-3? knockdown in vitro. Adipocyte precursors in 14-3-3? KO embryos also appear to have greater Gli3 and p27Kip1 abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3? is a critical upstream driver of adipogenesis.