This article examines contingencies and constraints in problem-solving processes underlying technological change and industry evolution. It shows how learning through practice can help drive technical change but, when this is impeded, the ability to make use of models and engage in experimental learning becomes even more pertinent for explaining variation in the rate and direction of technical change. The article explores HIV as an example of vaccine innovation, and vaccines as an example of medical innovation. I find the absence of these two variables (ability to learn directly in humans, and ability to learn vicariously through animal models) not only make up a large part of how I would characterize “difficulty” in the HIV R&D process, but they also seem to go a long way toward explaining why 33 other diseases have—or have not—had vaccines developed for them. Implications for theory and policy are discussed.