Histone deacetylases control cellular signaling and gene expression. Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses and is often significantly overexpressed in solid tumors. Nevertheless, transformed cells lacking HDAC2 due to somatic mutations have recently been discovered. This finding has raised a question regarding the functions of this enzyme. Detailed analyses of the molecular mechanisms governing gene regulation by HDAC2 illustrate how this protein influences proliferation, apoptosis and differentiation of cells. Beyond clarifying the role of HDAC2 for cellular fate, such data position the epigenetic regulator HDAC2 as a therapeutically important prognostic marker that can be subjected to pharmacological control.