Traditional explanatory clinical trials on well-regulated interventions (drugs, devices) are conducted following strict regulatory requirements that often hinder pre-approval trials to be naturalistic, thereby questioning their generalizability in various settings. Pragmatic (practical or effectivity) trials, on the other hand, aim to approximate the reality of everyday clinical practice and are critical to inform decision-making by patients, clinicians, and policymakers in real-world settings. In this chapter, we have highlighted real-world evidence generation, the drawbacks of explanatory or traditional clinical trials, key differences between explanatory (traditional) and pragmatic trials, dimensions for assessing the level of pragmatism in a clinical trial (pragmatic explanatory continuum indicator summary-2 tool), special designs of pragmatic trials (large simple trial and randomized database studies), and their common pitfalls. Pragmatic trials test interventions and assess patient-centered and hard outcomes in the full spectrum of everyday clinical settings in order to maximize their applicability and generalizability. However, their overt flexibility and heterogeneity, inviting serious risks of biases, sometimes puts their generalizability into question, especially in the era of patient-centered/personalized/precision medicine. Hence, both explanatory and pragmatic trials are essential to maintain the evidence pyramid.