Prevention and treatment of common noncommunicable chronic diseases have been revolutionized by the development of therapies. Recently, several randomized controlled trials (RCTs) designed to assess the efficacy of new therapies targeted at well-established risk factors for noncommunicable chronic diseases have reported lower benefits than expected. Subsequent observational analysis of the same trial data has not clarified these unexpected findings. Mendelian randomization (MR) provides an approach for estimating causal effects from observational or trial data and thus provides information complementary to that from an RCT. An RCT assesses the efficacy of a therapy but does not usually confirm the underlying mechanistic pathway. In contrast, an MR study does not assess the efficacy of a therapy but rather assesses causal effects on an underlying mechanistic pathway. We suggest that incorporating an MR study into an RCT at the design stage would improve etiologic understanding of current therapies and enhance the search for therapies for the significant amount of noncommunicable chronic diseases that resists current treatments.