The precise molecular strategies that coordinate patterns of transcriptional response to specific signals is central for understanding normal development and disease. Precise control of transcriptional programs underlying metazoan development is modulated by enzymatically active coregulatory complexes, coupled with epigenetic strategies. Epigenetic modifications, particularly DNA methylation and covalent histone modifications, for instance acetylation, methylation, phosphorylation and ubiquitination, play an essential role in transcription regulation, chromatin remodeling, genome instability and X chromosome inactivation. Recently, the ubiquitinases and deubiquitinases responsible for histone H2A ubiquitination and deubiquitination have been identified and characterized. These studies suggest that histone H2A ubiquitination play important roles in many cellular events, such as transcription initiation and elongation, silencing, and DNA repair. Alteration of histone H2A ubiquitination modifications may contribute human diseases, such as cancer. In this review, we discuss enzymes involved in H2A ubiquitination/deubiquitination and that possible molecular mechanisms underlying histone H2A ubiquitination/deubiquitination in transcriptional regulation and DNA damage repair.