Safety clinicians have a wealth of resources describing how to perform signal detection. Nevertheless, there are some nuances concerning approaches taken by regulatory authorities and statistical considerations that should be appreciated. New approaches, such as the FDA Medical Queries, illustrate the value of considering medical concepts over individual adverse events. One area which would benefit from further clarity is how safety signals may be evaluated for evidence of a causal relationship to the drug of interest. Just as such safety signals can take many forms, the types of tools and methods required to interrogate these signals are equally as diverse. An understanding of the complexity of this process can aid the safety reviewer in successfully characterizing the emerging safety profile of a drug during the pre-marketing phase of development.