The magnitude of the pathologist's role in the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) is underestimated. The diagnostic features are not specific to HNPCC cancers, but relate to all cancers showing high levels of DNA microsatellite instability (MSI-H). Three major groups of MSI-H cancers can be recognized by histopathological criteria: (1) right-sided poorly differentiated cancers, (2) right-sided mucinous cancers, and (3) adenocarcinomas in any location showing tumor-infiltrating (intraepithelial) lymphocytes (TIL). The poorly differentiated cancers are relatively well circumscribed and the cells are arranged in sheets or trabeculae. TIL may be very numerous in poorly differentiated cancers. The presence of TIL as estimated in H&E sections equates with a percentage of intraepithelial T cells (CD3+) in the range of 4 to 30%. Most of the T cells are CD8+ (cytotoxic T cells). Peritumoral lymphocytes and the so-called Crohn's-like reaction are associated with TIL, but are harder to quantify. Of the 15% of colorectal cancers that are MSI-H, 13% will be sporadic and 2% will occur in the context of HNPCC. HNPCC should be suspected if the patient is young (less than 55 years) because sporadic MSI-H cancers (associated with hypermethylation of the promoter region of hMLH1) occur almost exclusively in elderly subjects. Workup of a suspected case should include DNA microsatellite testing with a panel of mononucleotide (e.g., BAT26, BAT25) and dinucleotide (e.g., D5S346, D2S123, and D177S250) markers before referral to a cancer family or clinical genetics clinic. Immunohistochemical staining for hMLH1 and hMSH2 identifies the underlying mutation in a proportion of cases. The colorectal adenoma is the usual precursor lesion in HNPCC, though serrated polyps are implicated in a small subset.