The present invention provides novel ryanodine receptor type 2 (RyR2) inhibitors and methods of their use in the treatment of cardiac conditions. In general, the RyR2 inhibitors of the present invention assist in the normalization of intracellular calcium homeostasis. In certain embodiments, the RyR2 inhibitors are store-overload-induced Ca.sup.2+ release (SOICR) inhibitors that minimally inhibit or do not inhibit Ca.sup.2+-induced Ca.sup.2+ release (CICR), thereby providing beneficial effects in cardiac therapy.