We and others recently identified the gene metadherin (MTDH) as a functional driver in multiple aspects of cancer progression. It is overexpressed in cancer cells originating from a variety of tissues, partially due to DNA amplification of the chromosomal 8q22 region where this gene resides. The rapidly accumulated data from MTDH studies of the past several years have documented its role in tumorigenesis, angiogenesis, cell proliferation, survival, anchorage‐independent growth, metastasis and chemoresistance. In particular, it simultaneously helps the primary tumor cells to survive conventional chemotherapy and spread to distant organs, both of which are major contributors to cancer therapy failure and ultimately patient death. The efforts to elucidate the molecular mechanism of MTDH functions led to observations indicating its involvement in several prominent cancer‐related signaling pathways including Ras, c‐Myc, PI3K/AKT, NF‐κB, Wnt/β‐catenin, and more recently, microRNA machinery. Herein we will briefly summarize the studies that establish MTDH as a promising target for cancer therapeutics.