The BTB/POZ-ZF [Broad complex, Tramtrack, Bric à brac (BTB) or poxvirus and zinc finger (POZ)-zinc finger] protein family comprises a diverse group of transcription factors. POZ-ZF proteins have been implicated in many biological processes, including B cell fate determination, DNA damage responses, cell cycle progression and a multitude of developmental events, including gastrulation, limb formation and hematopoietic stem cell fate determination. Consequently, dysfunction of vertebrate POZ-ZF proteins, such as promyelocytic leukemia zinc finger (PLZF), B cell lymphoma 6 (Bcl-6), hypermethylated in cancer 1 (HIC-1), Kaiso, ZBTB7 and Fanconi anemia zinc finger (FAZF), has been linked directly or indirectly to tumorigenesis and developmental disorders. Here, we discuss recent advances in the POZ-ZF field and the implications for the design of future studies to elucidate the biological roles of these unique transcription factors.