In this review, Appel et al. provide an overview of the biophysical properties of the SPOC domain (Spen paralog and ortholog C-terminal domain), found in many proteins all across eukaryotic species, and its interaction with phosphorylated binding partners, the phylogenetic origin of SPOC domain proteins, the diverse functions of mammalian SPOC proteins and their homologs, the mechanisms by which they regulate differentiation and development, and their roles in cancer.