Very-high-cycle life qualification of prosthetic cardiac devices is an essential aspect of the overall device design, given long-term implant expectations, the inability to perform periodic inspection, and the serious consequences of device fracture. The International Standards Organization’s ISO 5840 and historical draft U.S. Food and Drug Administration guidance indicate that prosthetic heart valve structural components are expected to have a fatigue life in excess of 400 to 600 million cycles under worst-case physiological conditions. In the case of the design reliability qualification for a novel prosthetic cardiac device, a rigorous stress-life fatigue analysis based on the classical fatigue approach is recommended. Proven techniques that address a rigorous stress-life fatigue analysis include material fatigue-life determination based on extensive material specimen testing, the construction of constant-life curves incorporating mean stress versus stress amplitude using a generalized Weibull distribution, and model optimization using maximum likelihood methods. While this approach requires an extensive amount of effort, the results are widely applicable beyond the initial device qualification, and they may be used to evaluate design and boundary condition modifications. In the case of the limited risk qualification for minor changes to the materials or processing of a cardiac device, a fatigue-to-fracture or test-to-success approach may be appropriate. Proven techniques include whole device or whole component testing, with success or failure based on statistical evaluation using appropriate models. While this approach reduces the initial level of effort for a given assay, the results are typically limited to the specific design and material processing tested such that the initial testing will need to be repeated to evaluate any design or boundary condition modifications. The present paper provides a general framework and examples of the application of classical fatigue and fatigue-to-fracture techniques for very-high-cycle life qualification of prosthetic heart valve frames and other cardiac devices.