Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a multifaceted intracellular protein belonging to the evolutionarily conserved pleckstrin homology-related domain family. Its murine homologue, T-cell death-associated 51 (TDAG51) gene, was initially discovered for its role in activation-induced apoptosis in T-cell hybridomas. In recent years, PHLDA1 has received increased attention due to its association with obesity, fatty liver disease, diabetes, atherosclerosis, and cancer. Accumulating evidence also supports its role in endoplasmic reticulum stress signaling pathways as a crucial mediator of apoptosis, autophagy, and cell proliferation. In this review, the current knowledge of PHLDA1 gene and protein regulation, localization, and function is summarized. This review highlights the pro- and anti-apoptotic roles of PHLDA1 that contribute to vast array of metabolic diseases.