Many peptides are potent and highly selective blockers or modulators of calcium channel function, and as such are valuable pharmacological tools and potentially valuable leads for the development of human therapeutics. Cone shells and spiders are rich sources of such peptides, although they are also found in scorpions and insects. In this article we compare the amino acid sequences of toxins active against calcium channels and describe their three-dimensional structures and structure-function relationships. Certain structural motifs, in particular the inhibitor cystine knot, prove to be quite common amongst this class of toxins. Aspects of the pharmacology and physiology of these toxins in mammalian systems are also discussed, with an emphasis on their application in the treatment of chronic pain. We then consider the prospects for peptide-based therapeutics targeting calcium channels for this and other indications, including the development of non-peptide (peptidomimetic) compounds based on a detailed understanding of toxin structure-function relationships.