HAX-1 comprises a family of ubiquitously expressed proteins that play important roles in the regulation of programmed cell death. Herein, we provide a comprehensive review of the expression profile of HAX-1 and its functional implications during health and disease, highlighting its direct involvement in the development of congenital neutropenia and neural abnormalities, when absent, and its contribution to the progression of psoriasis and cancer, when overexpressed. Moreover, we provide new information on the differential expression of the HAX-1 subfamily in three distinct types of epithelial cancers, including breast, skin, and colon. Our results demonstrate a significant up-regulation of the anti-apoptotic HAX-1 variant 001 in skin and colon, but not in breast and cancer cells, indicating tissue-specific differences in its expression pattern and properties during cancer formation and progression. Our findings further reveal a considerable down-regulation, if not abrogation, of three distinct, yet to be characterized, HAX-1 isoforms in breast cancer cells, suggesting that they may function in an opposite manner to the anti-apoptotic variant 001. This study aims to summarize our current knowledge on the physiological implications of the expression profile of the HAX-1 subfamily in health and disease, and provide new information on the differential expression and activities of HAX-1 members in three distinct types of cancer. J. Cell. Physiol. 226: 2752–2761, 2011. © 2011 Wiley-Liss, Inc.