The RNA-binding proteins (RBPs) are critical trans factors that associate with specific cis elements present in mRNAs whose stability and translation are subject to regulation. The RBP Hu antigen R (HuR) is overexpressed in a wide variety of human cancers and serves as a prognostic factor of poor clinical outcome. HuR promotes tumorigenesis by interacting with a subset of oncogenic mRNAs implicated in different cancer hallmarks, and resistance to therapy. Reduction of HuR levels in cancer cells leads to tumor regression in mouse xenograft models. These findings prompt a working model whereby cancer cells use HuR, a master switch of multiple oncogenic mRNAs, to drive drug resistance and promote cell survival and metastasis, thus rendering the tumor cells with high cytoplasmic HuR more progressive and resistant to therapy. This review summarizes the roles of HuR in cancer and other diseases, therapeutic potential of HuR inhibition, and the current status of drug discovery on HuR.