Non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, enteric or other systemic infections, and stress have all been reported to be potential triggers of inflammatory bowel disease (IBD). Although a mechanism of triggering a flare of IBD can be hypothesized for each factor, the associations of these factors with flares of IBD remains confusing. In this review, we analyze the literature that explores these associations. There is some evidence to support an association between NSAID use and flares but little data to associate antibiotic use directly with flares. An important connection between antibiotic use and an exacerbation of symptoms is through the development of Clostridium difficile infections. However, for all enteric infections, including C. difficile, it is unclear whether these infections simply trigger symptoms in patients with IBD that resolve on resolution of the infection, or whether they truly trigger a flare of intestinal inflammation that outlasts the infection. There is a paucity of evidence that other systemic infections trigger flares of IBD. Although there is strong evidence for an association between perceived stress levels and flares, there is a weaker association between a simple accounting of stressful life events and flares. Much of the literature is limited by a lack of adequate control groups and failure to report on base rates in the population under study (i.e., NSAIDs and antibiotic use, occurrence of infections, and stress levels). More large population-based matched cohort or case crossover studies and a continued emphasis on prospective designs are needed to better explore these potential associations. Clinical implications given the current state of knowledge are discussed.