Comparative effectiveness research (CER) may be defined informally as an assessment of available options for treating specific medical conditions in selected groups of patients. In this context, the most prominent features of CER are the various patient populations, medical ailments, and treatment options involved in any particular project. Yet, each research investigation also has a corresponding study design or “architecture,” and in patient-oriented research a common distinction used to describe such designs are randomized controlled trials (RCTs) versus observational studies. The purposes of this overview, with regard to CER, are to (1) understand how observational studies can provide accurate results, comparable to RCTs; (2) recognize strategies used in selected newer methods for conducting observational studies; (3) review selected observational studies from the Veterans Health Administration; and (4) appreciate the importance of fundamental methodological principles when conducting or evaluating individual studies.