SET and MYND domain containing-3 (SMYD3) is a member of the lysine methyltransferase family of proteins, and plays an important role in the methylation of various histone and non-histone targets. Proper functioning of SMYD3 is very important for the target molecules to determine their different roles in chromatin remodeling, signal transduction and cell cycle control. Due to the abnormal expression of SMYD3 in tumors, it is projected as a prognostic marker in various solid cancers. Areas covered: Here we elaborate on the general information, structure and the pathological role of SMYD3 protein. We summarize the role of SMYD3-mediated protein interactions in oncology pathways, mutational effects and regulation of SMYD3 in specific types of cancer. The efficacy and mechanisms of action of currently available SMYD3 small molecule inhibitors are also addressed. Expert opinion: The findings analyzed herein demonstrate that aberrant levels of SMYD3 protein exert tumorigenic effects by altering the epigenetic regulation of target genes. The partial involvement of SMYD3 in some distinct pathways provides a vital opportunity in targeting cancer effectively with fewer side effects. Further, identification and co-targeting of synergistic oncogenic pathways is suggested, which could provide much more beneficial effects for the treatment of solid cancers.