After declining for decades, the incidence of Mycobacterium tuberculosis is increasing. The Mantoux tuberculin skin test, which uses purified protein derivative (PPD) of tuberculin, has been used for years as a screening device to detect the presence of exposure and infection to tuberculosis. However, the advent of human immunodeficiency virus (HIV) has elicited many questions regarding the validity of traditional standards for PPD administration and interpretation. The uncertainties in interpreting tuberculin skin tests in immunocompromised individuals is part of the challenge that is being faced by the health-care profession in this 2nd decade of acquired immune deficiency syndrome. This article will help advanced practice nurses understand the relationship between the immune system, tuberculosis, and the PPD skin test; the problem of anergy with immunocompromised patients, particularly those who are HIV-infected; issues involved in placement and interpretation of the results of the PPD test; new Agency for Health Care Policy and Research (AHCPR) standards for PPD interpretation with HIV-infected persons; the "booster" effect and two-step PPD testing; concerns regarding bacille Calmette-Guérin vaccine; and the use of a critical pathway to aid in rapid identification and isolation of the patient with HIV admitted with a potential diagnosis of tuberculosis versus Pneumocystis carinii pneumonia.