Compromised travelers represent a diverse and challenging group of individuals. They include HIV-infected patients who are at risk for potentially adverse reactions to immunizations, and new exposures to enteric water-borne opportunistic pathogens associated with chronic infections. Such travelers may encounter unfamiliar opportunistic fungi and classical tropical infections, such as leishmaniasis, whose pathogenesis can be enhanced by the presence of prior HIV infection. Other immunocompromised groups include those who are functionally or anatomically asplenic, and patients who are iatrogenically immunosuppressed from medications utilized for solid organ transplantation, chemotherapy, or treatment of malignancies. This population of travelers also includes those with diabetes mellitus who may require adjustments in their dosing, administration, and possibly even the types of insulin used on their trips. These patients are also at greater risk for acquisition of tuberculosis, severe community-acquired pneumonia, urinary tract infections, and pyomyositis. Older travelers present both the infectious disease and travel medicine specialist with issues such events, malignancy-related infections, myocardial infarction, and other forms of cardiopulmonary compromise, which the authors address in this article.