Eukaryotic protein kinases are key regulators of cell processes. Comparison of the structures of protein kinase domains, both alone and in complexes, allows generalizations to be made about the mechanisms that regulate protein kinase activation. Protein kinases in the active state adopt a catalytically competent conformation upon binding of both the ATP and peptide substrates that has led to an understanding of the catalytic mechanism. Docking sites remote from the catalytic site are a key feature of several substrate recognition complexes. Mechanisms for kinase activation through phosphorylation, additional domains or subunits, by scaffolding proteins and by kinase dimerization are discussed.