Recipients of hematopoietic stem cell transplants and solid organ transplants frequently develop pulmonary infiltrates from both infectious and non-infectious etiologies. Differentiation and further characterization of microbiologic etiologies—viral, bacterial, and fungal—can be exceedingly challenging. Pediatric patients face unique challenges as confirmatory evaluations with bronchoscopy or lung biopsy may be limited. A generalizable approach to diagnosing and managing these conditions has not been well established. This paper aims to summarize our initial clinical approach while discussing the relative evidence informing our practices. A pediatric patient with characteristic infiltrates who has undergone HSCT is presented to facilitate the discussion. Generalizable approaches to similar patients are highlighted as appropriate while highlighting considerations based on clinical course and key risk factors.