Abstract: The nuclear receptor Rev-erbα is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erbα mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erbα gene expression initially declines and subsequently increases. Remarkably, Rev-erbα protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erbα protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erbα protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erbα represses the expression of PPARγ2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erbα gene expression, Rev-erbα protein levels must rise and then fall for adipocyte differentiation to occur.