In this review, we describe the current knowledge of the biology of the JAKs. 
The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, 
and Tyk2, all key players in the signal transduction from cytokine receptors to 
transcription factor activation. We also review the progresses made towards the 
optimization of JAK inhibitors and the importance of their selectivity profile. 
Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray 
crystallography, scaffold morphing, etc.) has been deployed to successfully 
design molecules that discriminate among JAK family and other kinases. While the 
first JAK inhibitor was launched in 2011, this review also summarizes the status 
of several other small-molecule JAK inhibitors currently in development to treat 
arthritis, psoriasis, organ rejection, and multiple cancer types.