The human protein kinome comprises 535 proteins that, with the exception of 
approximately 50 pseudokinases, control intracellular signaling networks by 
catalyzing the phosphorylation of multiple protein substrates. While a major 
research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr 
kinases, over 85% of the kinome has been identified to be dysregulated in at 
least one disease or developmental disorder. Despite this remarkable statistic, 
for the majority of protein kinases and pseudokinases, there are currently no 
inhibitors progressing toward the clinic, and in most cases, details of their 
physiologic and pathologic mechanisms remain at least partially obscure. By 
curating and annotating data from the literature and major public databases of 
phosphorylation sites, kinases, and disease associations, we generate an 
unbiased resource that highlights areas of unmet need within the kinome. We 
discuss strategies and challenges associated with characterizing catalytic and 
noncatalytic outputs in cells, and describe successes and new frontiers that 
will support more comprehensive cancer-targeting and therapeutic evaluation in 
the future. Cancer Res; 78(1); 15-29. ©2017 AACR.