The family of homeodomain interacting protein kinases (HIPKs) consists of four related kinases, HIPK1 to HIPK4. These serine/threonine kinases are evolutionary conserved and derive from the yeast kinase Yak1. The largest group of HIPK phosphorylation substrates is represented by transcription factors and chromatin-associated regulators of gene expression, thus transferring HIPK-derived signals into changes of gene expression programs. The HIPKs mainly function as regulators of developmental processes and as integrators of a wide variety of stress signals. A number of conditions representing precarious situations, such as DNA damage, hypoxia, reactive oxygen intermediates and metabolic stress affect the function of HIPKs. The kinases function as integrators for these stress signals and feed them into many different downstream effector pathways that serve to cope with these precarious situations. HIPKs do not function as essential core components in the different stress signaling pathways, but rather serve as modulators of signal output and as connectors of different stress signaling pathways. Their central role as signaling hubs with the ability to shape many downstream effector pathways frequently implies them in proliferative diseases such as cancer or fibrosis.