This chapter highlights some landmark clinical trials fundamental to the practice of general internal medicine. Each study selected for inclusion addresses critical questions faced daily by clinicians, encompassing topics such as hypertension management (ALLHAT and SPRINT trials), cardiovascular prevention through statins (JUPITER trial), diabetes control and prevention of its complications (DCCT/EDIC trials), asthma management (SMART asthma trial), HIV treatment strategies (SMART HIV trial), the role and impact of palliative care interventions (SUPPORT trial), cancer screening efficacy (PLCO trial), chronic gastroesophageal reflux disease management (LOTUS trial), and the importance of diet and blood pressure control in chronic kidney disease (MDRD trial). By presenting comprehensive yet succinct summaries, including key results, clinical takeaways, practical bedside applications, and the influence of these studies on clinical guidelines, this chapter equips clinicians and trainees with the essential evidence needed to provide effective, evidence-based patient care across a wide range of common internal medicine scenarios.