Pediatric hematopoietic stem cell transplant patients are highly immune compromised with a significantly increased risk for severe pulmonary infections. In these two case reports, we review the use of plasma microbial cell-free DNA next generation sequencing, also known as the Karius Test (KT), as a non-invasive diagnostic tool. These cases illustrate how the KT can provide early species-level identification of pathogens for patients that are either unable to tolerate sedated bronchoscopy, or those with negative bronchoalveolar lavage due to heavy antibiotic pre-treatment. These two clinical cases illustrate how use of KT can reduce infection-related morbidity and mortality.