The transient receptor potential (TRP) channels are a large family of proteins with six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging from sensing of thermal and chemical signals to reloading intracellular stores after responding to an extracellular stimulus. Mutations in TRPs are linked to pathophysiology and specific diseases. An understanding of the role of TRPs in normal physiology is just beginning; the progression from mutations in TRPs to pathophysiology and disease will follow. In this review, we focus on two distinct aspects of TRP channel physiology, the role of TRP channels in intracellular Ca2+ homeostasis, and their role in the transduction of painful stimuli in sensory neurons.