Clinical trials have largely focused on whether an intervention can work. To ensure valid and powerful testing of this hypothesis, trials attempt to maximize the effect of the intervention of interest, controlling other factors that can confound comparisons. The benefits observed in these studies are often not sustained once the treatment is used in routine care, leaving regulators, practitioners and patients with a paucity of reliable evidence to assist decision-making. Attempts to address this need have led to ‘pragmatic trials’ that prioritize applicability of findings to real-world practice by minimizing design features that produce less pertinent information. Minimizing biases in this pragmatic context remains a very difficult task, however. This paper reviews some of these challenges and highlights specific aspects of design that must be approached with a pragmatic attitude.