Abstract Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented protein that exploits its kinase activity to modulate key molecular pathways in cancer to restrain tumor growth and induce response to therapies. HIPK2 phosphorylates oncosuppressor p53 for apoptotic activation. In addition, also p53-independent apoptotic pathways are regulated by HIPK2 and can be exploited for anticancer purpose too. Therefore, HIPK2 activity is considered a central switch in targeting tumor cells toward apoptosis upon genotoxic damage and the preservation and/or restoration of HIPK2 function is crucial for an efficient tumor response to therapies. As a proof of principle, HIPK2 knockdown impairs p53 function, induces chemoresistance, angiogenesis, and tumor growth in vivo, on the contrary, HIPK2 overexpression activates apoptotic pathways, counteracts hypoxia, inhibits angiogenesis, and induces chemosensitivity both in p53-dependent and -independent ways. The role of HIPK2 in restraining tumor development was also confirmed by studies with HIPK2 knockout mice. Recent findings demonstrated that HIPK2 inhibitions do exist in tumors and depend by several mechanisms including HIPK2 cytoplasmic localization, protein degradation, and loss of heterozygosity (LOH), recapitulating the biological outcome obtained by RNA interference studies in tumor cells, such as p53 inactivation, resistance to therapies, apoptosis inhibition, and tumor progression. These findings may lead to new diagnostic and therapeutic approaches for treating cancer patients. This review will focus on the last updates about HIPK2 contribution in tumorigenesis and cancer treatment.