Homeodomain interacting protein kinase 2 (HIPK2) functions as either a co-repressor or a co-activator of transcriptional regulators. Dysregulation of HIPK2 is associated with cancer and neurological disease. Recently, we found that HIPK2 is also an important driver of kidney fibrosis in the HIV-1 transgenic murine model, Tg26. HIPK2 protein levels are upregulated in the tubular epithelial cells of Tg26 mice as well as in kidney biopsies of patients with HIV-associated nephropathy, focal segmental glomerulosclerosis, diabetic nephropathy, and IgA nephropathy. We found that HIPK2 regulates pro-apoptotic, pro-fibrotic, and pro-inflammatory pathways including p53, transforming growth factor β (TGF-β)–SMAD family member 3 (Smad3), Notch, Wingless and INT-1 (Wnt)/β-catenin, and nuclear factor kappa-light-chain-enhancer of activated B cells in renal tubular epithelial cells. Our data suggest that HIPK2 may be a potential target for antifibrotic therapy. As mice with germline deletion of HIPK2 do not exhibit any phenotypic change under basal conditions, we do not expect significant side effects with specific HIPK2 inhibitors. However, potential effects of HIPK2 on tumor growth should be considered because of its tumor suppressor effects. Therefore, further understanding of structure–function relationships and post-translational modifications of HIPK2 are necessary to develop more specific drugs targeting the pro-fibrotic effects of HIPK2.