Protein kinases are known primarily for their ability to phosphorylate protein 
substrates, which constitutes an essential biological process. Recently, 
compelling evidence has accumulated that the functions of many protein kinases 
extend beyond phosphorylation and include an impressive spectrum of 
non-catalytic roles, such as scaffolding, allosteric regulation, or even 
protein-DNA interactions. How the conserved kinase fold shared by all metazoan 
protein kinases can accomplish these diverse tasks in a specific and regulated 
manner is poorly understood. In this review, we analyze the molecular mechanisms 
supporting phosphorylation-independent signaling by kinases and attempt to 
identify common and unique structural characteristics that enable kinases to 
perform non-catalytic functions. We also discuss how post-translational 
modifications, protein-protein interactions, and small molecules modulate these 
non-canonical kinase functions. Finally, we highlight current efforts in the 
targeted design of small-molecule modulators of non-catalytic kinase functions, 
a new pharmacological challenge for which structural considerations are more 
important than ever.