Certain types of colitides, such as collagenous colitis, lymphocytic colitis, and ischemic colitis, have distinct histologic features that allow for a specific diagnosis. However, in most colonic biopsy specimens, a definite diagnosis cannot be established on the basis of histology alone. Thus, in most cases of colitis, it is helpful to utilize a systematic approach in order to recognize patterns of injury. This information in conjunction with clinical and laboratory findings may help pathologists narrow the differential diagnosis and/or establish a more definite etiology for the patient’s illness in order to guide clinical management. We provide general guidelines to distinguish variations in normal mucosa and biopsy procedure-related artifacts from true inflammatory conditions. Inflammatory conditions may be further categorized into those with predominantly lymphoplasmacytic inflammation (with or without neutrophils), predominantly neutrophilic inflammation, predominantly eosinophilic inflammation, or paucicellular colitis, since each of these patterns of inflammation are associated with a distinct differential diagnosis. This review will focus on a pattern-based algorithmic approach to evaluating biopsies of patients who present to physicians with signs and symptoms of colitis.