A basic tenet of science is an acceptance of uncertainty. This may seem to be a glaringly obvious point, but there must be a degree of uncertainty prior to achieving any type of real progress, even in the medical sciences. If we knew everything in advance, it would be hard to stake a claim that we’ve made steps forward. The problem is that our relationship with uncertainty has dwindled. Chapter 21 reflects on topics from previous chapters, including warped incentive structures, short-term thinking, and inflexible funding structures, and how they represent a growing unacceptance of uncertainty. The chapter concludes with reflecting on how this is likely to affect the rate and direction of progress.