Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace and is characterized by an accumulation of beryllium‐specific CD4⁺ T cells with granulomatous inflammation in the lung. Owing to its unique physical properties, beryllium is used in a variety of high‐technology industries, and CBD continues to be an important public health concern. CBD develops in up to 16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Increased susceptibility has been associated with particular HLA‐DP alleles, especially those possessing negatively charged residues at certain positions of the peptide‐binding pocket. The mechanism for this disease association lies in the ability of certain HLA‐DP molecules, with associated peptides, to bind and present beryllium to pathogenic CD4⁺ T cells. In patients with CBD, large numbers of effector memory CD4⁺ T cells are compartmentalized to the lung, and these cells are poised to release T helper 1‐type cytokines upon beryllium recognition. In the same patients, however, beryllium‐specific T cells are barely detectable in the circulation. As opposed to those present in blood, beryllium‐specific cells in the lung no longer require the engagement of CD28 for optimal T‐cell activation and in fact frequently lose the expression of CD28. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the antigen is unknown and the target organ is inaccessible.