Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine protein kinase that participates in the regulation of diverse cellular activities as a transcriptional cofactor and signal transducer. HIPK2 senses various signaling cues that in turn phosphorylate downstream substrates to coordinate developmental processes, cell cycle regulation, cell proliferation, differentiation, and the DNA damage response. HIPK2 functions are affected by its catalytic activity, stability, and subcellular localization, which in turn are dynamically regulated by diverse post-translational modifications such as polyubiquitination, SUMOylation, phosphorylation, and acetylation. HIPK2 is not modified with small molecules and/or peptides individually or independently, but in a combinatorial manner that is referred to as the “HIPK2 modification code.” HIPK2 integrates various signaling cues and senses different doses of DNA damage and ROS stimuli, which are reflected by unique patterns of HIPK2 modification. Hence, the HIPK2 modification code differentially contributes to cellular homeostasis and determination of cell fate depending on cellular context.