The calcium-sensing receptor (CaSR) must function in the chronic presence of agonist, and recent studies suggest that its ability to signal under such conditions depends upon the unique mechanism(s) regulating its cellular trafficking. This chapter will highlight the evidence supporting an intracellular endoplasmic reticulum-localized pool of CaSR that can be mobilized to the plasma membrane by CaSR signaling, leading to agonist-driven insertional signaling (ADIS). I summarize evidence for the role of small GTP binding proteins (Rabs, Sar1 and ARFs), cargo receptors or chaperones (p24A, RAMPs) and interacting proteins (14-3-3 proteins, calmodulin) in anterograde trafficking of CaSR, and discuss the potential signaling specializations arising from CaSR interactions with caveolins or Filamin A/Rho. Finally, I summarize current knowledge about CaSR endocytosis and degradation by both the proteasome and lysosome, and highlight recent studies indicating that defective trafficking of CaSR or interacting protein mutants contributes to pathology in disorders of calcium homeostasis.