Adipocyte differentiation is a well defined process that is under the control of transcriptional activators and repressors. We show that histone deacetylase (HDAC) inhibitors efficiently block adipocyte differentiation in vitro. This effect is specific to adipogenesis, as another mesenchymal differentiation process, osteoblastogenesis, is enhanced upon HDAC inhibition. Through the systematic genetic deletion of HDAC genes in cultured mesenchymal precursor cells, we show that deletion of HDAC1 and HDAC2 leads to reduced lipid accumulation, revealing redundant and requisite roles of these class I HDACs in adipogenesis. These findings unveil a previously unrecognized role for HDACs in the control of adipogenesis.