Bromodomain and extra terminal (BET) proteins comprise the ubiquitously expressed BRD2, BRD3, BRD4 and the testes specific BRDT. These multipurpose proteins contain tandem N-terminal bromodomains that bind acetylated lysine residues of histone (and non-histone) proteins and other protein modules, such as the extra terminal domain, and in some (BRD4, BRDT), a C-terminal domain. They also mediate a number of effects including transcriptional activation via recruitment of other partner proteins. Inhibitors of these proteins are emerging as exciting new therapies for the treatment of hematologic and solid malignancies, offering the possibility of specifically targeting epigenetic readers. We and others have already demonstrated the preclinical efficacy of BET inhibitors in acute myeloid leukemia (AML), while several other papers have documented similar efficacy in myeloma, non-Hodgkin lymphoma, and acute lymphoblastic leukemia. These observations have led to several clinical trials that are currently underway to confirm the efficacy of these drugs in AML and other malignancies. Even though the most mature trials have recently reported limited objective responses of monotherapy in heavily pre-treated AML, lymphoma and myeloma patients, early data suggest that combination therapies with other small molecules or more conventional cytotoxic agents might be particularly promising.