The review examines the relationship between the structure of several ryanodine analogs and (A) binding, (B) channel conductance, and (C) ligand binding kinetics. Comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) are used to quantitatively assign structural correlations. Hydrogen bond donating (but not accepting) ability was found to be highly correlated with ligand affinity. Analysis of the correlation between hydrophobicity and ligand affinity indicates that, in general, deviation from the amphipathic nature of ryanodine weakens binding. Affinities and binding kinetics obtained in vivo are comparable to those obtained in the less-than-physiological in vitro conditions. Therefore, the structure-activity relationships surveyed are relevant to the living cell. The review presents arguments favoring the propositions that (A) the pyrrole is a major factor orienting the ligand in the receptor binding site and (B) that ryanoids alter ryanodine receptor function through allosteric mechanisms.