We recently identified the second of three SPRY domains in the skeletal muscle ryanodine receptor type 1 (RyR1) as a potential binding partner in the RyR1 ion channel for the recombinant II-III loop of the skeletal muscle dihydropyridine receptor, for a scorpion toxin, Imperatoxin A and for an interdomain interaction within RyR1. SPRY domains are structural domains that were first described in the fungal Dictyostelium discoideum tyrosine kinase spore lysis A and all three isoforms of the mammalian ryanodine receptor (RyR). Our studies are the first to assign a function to any of the three SPRY domains in the RyR. However, in other systems SPRY domains provide binding sites for regulatory proteins or intramolecular binding sites that maintain the structural integrity of a protein. In this article, we review the general characteristics of a range of SPRY domains and discuss evidence that the SPRY2 domain in RyR1 supports interactions with binding partners that contain a structural surface of aligned basic residues.