Over the last decade, the functions of PHD finger protein 20 (PHF20) in several signaling processes have been studied, including those of protein kinase B (PKB)-mediated phosphorylation, p53 regulation, muscle differentiation, and histone modification including histone H3 lysine 4 (H3K4) methylation. One PHF20 human mutation lacks the first nonspecific lethal complex of the component that binds to H3K4me2 to facilitate cancer cell survival. In carcinoma cells, PHF20 expression is regulated by PKB; PHF20 becomes phosphorylated when DNA is damaged, thus inhibiting the p53 activity that maintains cancer cell survival. Given this regulatory effect, PHF20 is usually expressed not only in gliomas but also in breast cancers, colorectal cancers, and other diseases associated with skeletal muscle osteoblastosis and osteoporosis. Thus, PHF20 dysregulation and its downstream effects enhance the abnormalities associated with cancers or other diseases and encourage disease progression. Moreover, PHF20 serves as a nuclear factor kappa-light-chain enhancer of B cell activation, thus increasing pro-inflammatory cytokine production, associated with crosstalk involving the mouse double minute 2 homolog that in turn reduces the normal p53 levels not only in cancers but also in damaged or otherwise injured normal tissues. Despite the findings of various studies, the roles of PHF20 in terms of prognosis, diagnosis, and targeting of disease therapies remain unclear and should be further explored.