The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.