The calcitonin receptor (CTR) and calcitonin-like receptor (CLR) are two of the fifteen human family B (or Secretin-like) G protein-coupled receptors (GPCRs). CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins (RAMPs). They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with RAMPs adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and reccurring themes and how such findings relate to two unusual but important receptors, CTR and CLR.