Epigenetic regulation of gene expression is strongly influenced by the accessibility of nucleosomal DNA or the state of chromatin compaction. In this context, coregulators, including both coactivators and corepressors, are pivotal intermediates that bridge chromatin-modifying enzymes and transcription factors. NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are among the best-characterized corepressors from a molecular point of view. These coregulators have conserved orthologs in lower organisms, which underscores their functional importance. Here we summarize the results from recent in vivo studies that reveal the wide-ranging roles of NCoR1 and SMRT in developmental as well as homeostatic processes, including metabolism, inflammation, and circadian rhythms. We also discuss the potential implications of NCoR1 and SMRT regulation of pathways ranging from genomic stability and carcinogenesis to metabolic diseases such as type 2 diabetes.