Salt-inducible kinases (SIKs) represent a subfamily of AMP-activated protein kinase (AMPK) family kinases. Initially named because SIK1 (the founding member of this kinase family) expression is regulated by dietary salt intake in the adrenal gland, it is now apparent that a major biological role of these kinases is to control gene expression in response to extracellular cues that increase intracellular levels of cAMP. Here, we review four physiologically relevant examples of how cAMP signaling impinges upon SIK cellular function. By focusing on examples of cAMP-mediated SIK regulation in gut myeloid cells, bone, liver, and skin, we highlight recent advances in G protein-coupled receptor (GPCR) signal transduction. New knowledge regarding the role of SIKs in GPCR signaling has led to therapeutic applications of novel small molecule SIK inhibitors.