Central nervous system (CNS) infections in cancer patients present a diagnostic and therapeutic challenge for clinicians. While CNS infections are not frequent complications of cancer, its therapies, or hematopoietic stem cell transplantation, the importance of CNS infections lies in their propensity to result in profound morbidity and substantial mortality in this vulnerable patient population. With an expanding population of patients with malignant disease undergoing more potent and aggressive therapies and with the advent of newer immunomodulatory agents, the incidence of CNS infectious complications is likely to rise. This chapter will summarize the clinical and diagnostic evaluation of potential infections of the CNS in these patients and will discuss particular pathogens of interest with regard to this at-risk patient population.