BCR-ABL1 tyrosine kinase inhibitors (TKIs) have dramatically transformed the treatment of patients with chronic myelogenous leukemia (CML). Given the impressive and sustained response to TKI therapy that the majority of treated patients with CML enjoy, recent studies have explored the potential to achieve treatment-free remission in select patients, which may allow these patients to escape the adverse clinical and financial effects associated with life-long TKI therapy. The results of multiple prospective trials have demonstrated that patients who maintain a deep molecular response for at least 2 years with TKI treatment may be eligible for trial of TKI discontinuation. Mounting data indicates that approximately 40% of those who discontinue therapy on trial will remain in remission at least 1 year after TKI discontinuation; the majority of patients with molecular recurrence relapse within the first 6 months after TKI discontinuation, and TKI retreatment is highly effective in restoring response. Sokol score, duration of TKI therapy, depth of molecular response, and the presence of natural killer cells may all be associated with a higher probability of attaining treatment-free remission. Moving forward, emerging data from ongoing TKI discontinuation trials will allow for appropriate selection of patients with CML eligible for this approach, will expand our current understanding of the CML stem cell, and identify therapeutic interventions capable of effectively deleting the malignant hematopoietic stem cell.