Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment paradigm of relapsed/refractory B-cell malignancies. Yet, this therapy is not without toxicities. While the early inflammation-mediated toxicities are now better understood, delayed hematopoietic recovery and infections result in morbidity and mortality risks that persist for months following CAR-T. The predisposition to infections is a consequence of immunosuppression from the underlying disease, prior therapies, lymphodepletion chemotherapy, delayed hematopoietic recovery, B-cell aplasia, and delayed T-cell immune reconstitution. These risks and epidemiology can vary over a post-CAR-T timeline of early (<30 days), prolonged (30-90 days), or late (>90 days) follow-up. Antibacterial, antiviral, and antifungal prophylaxis; growth factors and stem cell boost to expedite count recovery; immunoglobulin replacement therapy; and possibly revaccination programs are important prevention strategies to consider for infection mitigation. Assessment of risk factors, evaluation, and treatment for pathogen(s) prevalent in a particular time frame post-CAR-T are important clinical considerations in patients presenting with clinical features suggestive of infectious pathology. As more data emerge on the topic, personalized risk assessments to inform the type and duration of prophylaxis use and planning interventions will continue to emerge. Herein, we review our current approach toward infection mitigation while recognizing that this continues to evolve and that there are differences among practices stemming from data availability limitations.