This review provides a summary of common diagnostic problems encountered by both pathologists and gastroenterologists when evaluating patients with diarrhea and in whom inflammatory bowel disease (IBD) is suspected. The two most common forms of IBD, ulcerative colitis (UC) and Crohn's disease (CD), may, in certain settings, show overlapping endoscopic and pathologic features, potentially resulting in diagnostic confusion. For instance, some cases of UC may show unusual CD-like features, such as rectal sparing, discontinuous disease, aphthous ulceration, ileal or extracolonic involvement, and granulomatous inflammation, all of which may be evident in mucosal biopsy specimens. CD may also present as a diffuse, superficial pancolitis with ileal sparing that mimics the endoscopic and histologic appearance of UC. Furthermore, other forms of colitis, such as microscopic colitis, diverticulitis, diversion colitis, and nonsteroidal anti-inflammatory drug (NSAID)-induced colonic injury may also show IBD-like changes in mucosal biopsies. The potential diagnostic pitfalls faced by physicians, as well as features that aid in the distinction among these entities, are discussed in detail in this review.