Many effective therapeutic options are available for patients with chronic myelogenous leukemia (CML). Imatinib, a first-generation tyrosine kinase inhibitor (TKI), is one of several options for patients who present with CML, whether in chronic phase, accelerated phase, or blast crisis. Although CML is very responsive to the selective TKIs, with response rates in chronic phase of greater than 90%, unusual presentations have been documented. Response rates for patients with CML in accelerated phase and blast crisis are notably lower to both first- and second-generation TKIs. This report presents a recent case of a young woman with newly diagnosed CML who presented with an accelerated phase isolated central nervous system (CNS) relapse after standard imatinib therapy, who initially experienced a complete hematologic response. Further treatment options, and monitoring of disease response, are discussed. Aggressive strategies, such as intrathecal chemotherapy, change in tyrosine kinase inhibitor to one with increased CNS penetration, and consideration of allogenic stem cell transplantation, are potential therapeutic modalities. Prophylaxis of the CNS in patients deemed at risk is an area requiring further study.