The importance of randomized controlled trials (RCTs) versus observational studies has been debated for several years. However, the question is not whether RCTs are better than observational study designs. RCTs certainly provide the most unbiased answers in scenarios where it is logistically and ethically feasible to conduct both RCTs and observational studies. That is, study design is not a choice but a function of matching the research question to provide the most unbiased answers. The basic concept that underpins every clinical research project is the requirement of a clearly defined research question domain. Broadly, the clinical research question domain relates to prognosis, diagnostic accuracy, treatment or adverse events. While RCTs provide the most unbiased answers on questions related to the efficacy of treatments, other designs are better suited to answer questions related to prognosis or diagnostic accuracy of tests. In this paper, we illustrate the significance of matching study design to the research question domain while using clinical scenarios as an example. Although there are several other question domains that also concern the practice of medicine, we are only focusing on study designs concerning the issue of prognosis and diagnostic accuracy in this paper.