Pleuropulmonary blastoma (PPB) is the most common primary lung tumor of childhood and is associated with somatic or germline DICER1 variants. Recurrent PPB, especially with brain metastases, are difficult to treat and survival is poor. Comprehensive genomic analyses of PPB have been limited in number and depth. The cases presented here identified additional oncogenic drivers from tumor sequencing that could be modulating tumor progression and response to therapy outside of known DICER1 mutations highlighting the need for upfront genomic analysis on all patients with PPB.