--- - |2- Abstract MicroRNAs (miRNAs) are an important class of endogenous small noncoding single‐stranded RNAs that suppress the expression of their target genes through messenger RNA (mRNA) degradation to inhibit transcription and translation. MiRNAs play a crucial regulatory role in many biological processes including proliferation, metabolism, and cellular malignancy. miR‐15a/16 is an important tumor suppressor gene cluster with a variety of factors that regulate its transcriptional activity. It has been discovered that a relative reduction of miR‐15a/16 expression in various cancers is closely related to the occurrence and progression of tumors. miR‐15a/16 takes part in a wide array of biological processes including tumor cell proliferation, apoptosis, invasion, and chemoresistance by binding to the 3′‐untranslated region of its target gene's mRNA. In this review, we will examine the complex regulatory network of miR‐15a/16 gene expression and its biological functions in human cancers to further elucidate the molecular mechanisms of its antitumor effects. - Journal of Cellular Physiology, EarlyView.