In this article, we review the criteria used to establish a causal association. A literature search strategy will be outlined. We present a clinical scenario that was formulated to examine the evidence for nonsteroidal anti-inflammatory drugs as a possible cause of gastrointestinal ulceration and bleeding. Several of the studies identified in the literature search were critically appraised and the criteria needed to confirm a causal link were then applied. These guidelines may be employed to not only demonstrate the aetiology of a disease but have wider applicability in terms of determining whether a medication may be causing certain adverse events.