Voltage-gated calcium channels are found in all excitable cells, in which they regulate many important physiological functions, including excitability, gene transcription, muscle contraction, and neurotransmitter and hormone release. The differential modulation of calcium channels by intracellular second messengers constitutes a key mechanism for controlling calcium influx. Recent advances have provided important clues to the underlying molecular mechanisms involved in the inhibition of N-type and P/Q-type calcium channels by a membrane-delimited G-protein-dependent pathway.