Preferred tests for the diagnosis of Johne's disease are divided into two major categories:(I) agent detection; (ii) specific serum antibody/cell-mediated immunity detection. Agent detection tests include bacterial culture, genetic probes and biopsy. Many of the presently used tests suffer from inability to target early infection with Mycobacterium paratuberculosis. Early detection of Johne's disease by biopsy of intestine and/or draining mesenteric lymph nodes is based on the observation of inflammatory changes and/or acid-fast bacilli resembling Mycobacterium paratuberculosis in target tissues. Pathognomonic cellular changes include clustered epithelioid macrophages and/or individual or several inflammatory giant cells of Langhans' type (L type). These cells may have phagocytized one or more acid-fast bacilli. The ideal tissue to harvest is mesenteric lymph node. The most significant hallmark for early diagnosis is the Langhans' type giant cell located in the paracortical zone of the mesenteric lymph node. Pathologists are divided as to the criteria needed for a confirmatory diagnosis of early Johne's disease. Uniformly accepted guidelines for the positive diagnosis should be established and adhered to by pathologists. There is a void not only for uniformity of interpretation, but also for establishing sensitivity and specificity for the biopsy as diagnostic tool. The tissue obtained through biopsy can be additionally used for immunohistochemistry, genetic probes and culture of infectious bacilli. In conjunction with the herd history the biopsy has potential usefulness as a diagnostic test for screening individual animals under consideration for addition to paratuberculosis negative collections of zoo artiodactyla or cattle herds with infection negative status. Despite the cost and labour-intensity (laparotomy) the biopsy could become a valuable test for the control of paratuberculosis. This presentation will demonstrate histopathologic examples of early Johne's disease and pitfalls of interpretation.