This chapter discusses the broad categories of clinical investigations used in post-market drug safety assessment. It presents the three main methods of clinical post-marketing safety assessment: case reports and case series; observational epidemiological studies; and clinical trials. Active surveillance systems are also being explored to identify and examine drug safety issues. Drug safety active surveillance systems, which take advantage of large repositories of automated healthcare data, are now being developed and tested by multiple organizations. The two most common observational epidemiological study designs are the case-control design and the cohort design. The majority of clinical trials are performed primarily to assess the efficacy of a product. The design of a post-marketing clinical trial testing a safety hypothesis is often an active-controlled trial that uses a non-inferiority study design. Relative to observational epidemiological studies, clinical trials designed to answer drug safety questions are usually more costly and more time-consuming.