Since calcification limits the durability of contemporary bioprosthetic heart valves, antimineralization treatments are being widely investigated. Potential antimineralization treatments must have sustained prevention of mineralization without adverse effects. The preclinical investigation of efficacy and safety of antimineralization treatments comprises four essential steps: (1) subcutaneous implantation in small animals, (2) in vitro biomechanical studies of hemodynamics and durability, (3) morphology of unimplanted valves, and (4) circulatory implants in large animals.