The salt-inducible kinases, SIK1, SIK2 and SIK3, most closely resemble the 
AMP-activated protein kinase (AMPK) and other AMPK-related kinases, and like 
these family members they require phosphorylation by LKB1 to be catalytically 
active. However, unlike other AMPK-related kinases they are phosphorylated by 
cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 
14-3-3 proteins and inactivation. The most well-established substrates of the 
SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 
2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the 
translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 
14-3-3s, preventing them from regulating their nuclear binding partners, the 
transcription factors CREB and MEF2. This process is reversed by PKA-dependent 
inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a 
HDACs and their re-entry into the nucleus. Through the reversible regulation of 
these substrates and others that have not yet been identified, the SIKs regulate 
many physiological processes ranging from innate immunity, circadian rhythms and 
bone formation, to skin pigmentation and metabolism. This review summarises 
current knowledge of the SIKs and the evidence underpinning these findings, and 
discusses the therapeutic potential of SIK inhibitors for the treatment of 
disease.