The receptor class Frizzled, which has recently been categorized as a separate group of G protein-coupled receptors by the International Union of Basic and Clinical Pharmacology, consists of 10 Frizzleds (FZD(1-10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH). Recent years have seen major advances in our knowledge about these seven-transmembrane-spanning proteins, including: receptor function, molecular mechanisms of signal transduction, and the receptor's role in embryonic patterning, physiology, cancer, and other diseases. Despite intense efforts, many question marks and challenges remain in mapping receptor-ligand interaction, signaling routes, mechanisms of specificity and how these molecular details underlie disease and also the receptor's important role in physiology. This review therefore focuses on the molecular aspects of WNT/FZD and HH/SMO signaling discussing receptor structure, mechanisms of signal transduction, accessory proteins, receptor dynamics, and the possibility of targeting these signaling pathways pharmacologically.