DNAJB6 also known as mammalian relative of DnaJ (MRJ) encodes a highly conserved member of the DnaJ/Hsp40 family of co-chaperone proteins that function with Hsp70 chaperones. DNAJB6 is widely expressed in all tissues, with higher expression levels detected in the brain. DNAJB6 is involved in diverse cellular functions ranging from murine placental development, reducing the formation and toxicity of mis-folded protein aggregates, to self-renewal of neural stem cells. Involvement of DNAJB6 is implicated in multiple pathologies such as Huntington's disease, Parkinson's diseases, limb-girdle muscular dystrophy, cardiomyocyte hypertrophy and cancer. This review summarizes the important involvement of the spliced isoforms of DNAJB6 in various pathologies with a specific focus on the emerging roles of human DNAJB6 in cancer and the underlying molecular mechanisms.