(Jenden and Fairhurst, 1969), appeared in this Journal. During this time, we have learned a great deal about ryanodine and related compounds, and about ryanodine receptor (RyR) c calcium release channels, the family of proteins that bind and are modified by these ligands. The interest in the pharmacology of the RyRs has increased as these proteins have been shown to serve as intracellular Ca2+ release channels in a variety of tissue and cell types (Sutko and Airey, 1996). Moreover, as discussed in this review, several important questions remain concerning the role of RyR-mediated Ca2+ release events in different cell types, and the channel properties of different RyR isoforms. Resolution of these questions will require, at least in part, the use of pharmacological agents that modify the activity of the RyRs in both channel property-and isoform-specific ways. Recent data suggest it will be possible to develop such agents. Compounds related to ryanodine, termed ryanoids, exhibit agonist-and antagonist-like actions on RyR channels and, if not provided by nature, have the potential to be made RyR isoform-specific by chemical engineering. In addition, new agents that affect RyR channels, many of which are chemically unrelated to ryanodine, are being identified at a rapid rate. In this article, we focus on the present state of RyR pharmacology and consider the aspects of RyR function that require the development of RyR isoform-specific RyR channel modifiers. Ryanodine and related compounds will receive much of our attention, as they remain the prototypic and most potent modulators of the RyR family of proteins. We will also limit our consideration to vertebrate RyRs. As noted below, the ryanoids are commercially important pesticides, and the effects of these agents on insects have been discussed previously (Crosby, 1971; Pessah, 1990; Jefferies and Casida, 1994).