There are several methods in which one can assess the relationship between an intervention and an outcome. Randomized controlled trials (RCTs) are considered as the gold standard for evaluating interventions. However, for many questions of clinical importance, RCTs would be impractical or unethical. Clinicians must rely on observational studies for the best available evidence when RCTs are unavailable. This article provides an overview of observational research designs to facilitate the understanding and appraising of their validity and applicability in clinical practice. Major methodological issues of observational studies including selection bias and confounding are also discussed. In addition, strategies to minimize these problems in the design and analytical phases of a study are highlighted. Knowledge of the strengths, weaknesses and recent methodological advances in observational studies can assist clinicians to make informed decisions about whether a particular observational study would provide useful information to enhance patient care.