Casein Kinases are named after the use of casein as a convenient substrate for experimental examination of kinase activity. The CK1s represent a typically small but essential ePK group found in all eukaryotes. The CK1 is enormously expanded in C. elegans. Mammalian CK1 isoforms phosphorylate many different substrates among them key regulatory proteins involved in the control of cell differentiation, proliferation, chromosome segregation and circadian rhythms. CK1 deregulation and/or the introduction of mutations in their coding sequences have been linked to cancer and neurodegenerative diseases, such as Alzheimers and Parkinsons disease, and sleeping disorders. CK1 kinase activity is modulated by extracellular stimuli, the subcellular localization of CK1 isoforms, interaction with various cellular structures and proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains.