Pediatric non-Hodgkin lymphoma (NHL) is a common and fascinating group of diseases with distinctive underlying genetic events that characterize the major histologic subtypes: diffuse large B-cell lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma and lymphoblastic lymphoma. With systematic improvements in therapy over recent decades, the vast majority of children with NHL of all subtypes are now cured. The similarities and differences between adult and childhood presentations of disease, and whether or not some subtypes of NHL and leukemia are the same or different disease entities, are interesting questions that will be addressed with advances in our understanding of the molecular and genetic bases of these diseases. As is the case with other pediatric malignancies, growing emphasis is now being placed on the development of less toxic, targeted therapeutic approaches, and this review highlights some of the biological discoveries that will potentially open these avenues.