Precision medicine, the individualization of health care based on unique patient-specific variables, is not new, especially within oncology. Historically, there has been a “depersonalization” of cancer care by defining histotype-specific standard-of-care treatments for the majority of malignancies, although in contrast oncologists have been adept at individualizing therapy, especially when confronted with disease relapse. Practicing oncologists seek evidence-based approaches to improve patient outcomes, but much of the current personalization of care remains largely empirical. Nevertheless, over the past decade there has been increasing enthusiasm for using genomic data to more precisely diagnose cancer, predict outcomes, and prescribe “targeted” therapies. Although substantial progress has been made, both anticipated and unanticipated barriers exist in integrating sequencing technologies into the care of patients with cancer. Clearly, for multiple reasons, many challenges remain to prove that personalized genomic medicine can substantively improve outcomes for patients with cancer. These challenges are further accentuated with childhood cancers.