Management of patients with central nervous system tumors relies largely on magnetic resonance imaging scans to document disease progression or recurrence. The finding of new lesions always presents the challenge of differentiating between post-surgical changes, radiation necrosis, gliosis, and tumor, submitting these patients to more aggressive therapy and more toxicity. We reviewed the medical records of three patients with primary central nervous system tumors treated at the Children's Hospital Los Angeles who had new false-positive magnetic resonance imaging findings suggestive of tumor recurrence. All of them had complete total resection of primary tumor, had received involved-field radiation therapy, had biopsies confirming absence of viable tumor, and all three patients are long-term survivors. These cases exemplify that not everything that enhances on brain or spine magnetic resonance imaging is viable tumor, and a biopsy should always be considered in the decision-making process in evaluation of potentially recurrent central nervous system tumors in pediatric patients. A step-wise approach for such challenging cases is presented in this article.