The therapeutic armamentarium for chronic myeloid leukaemia (CML) comprises mainly tyrosine kinase inhibitors (TKIs), with several agents available for frontline treatment, or for the treatment of disease resistance or intolerance to the first-choice or second-choice drug. The availability of different drugs is a major achievement, but means that choices must be made — which can be difficult and questionable at times. The most important end point considered in decision-making regarding treatment for any cancer is overall survival, but additional factors (such as age, prognostic category, safety, or the possibility of achieving treatment-free remission) should be considered when selecting an agent for frontline treatment. Regardless of the TKI selected for first-line treatment, guidelines that define the importance of reaching specific response indicators and procedures for vigilant follow-up monitoring are established to ensure timely implementation of second-line TKIs. Herein, we discuss the benefits and risks of the different TKIs available for the treatment of patients with CML, and how to decide when to employ these agents at different treatment settings.