The management of chronic myeloid leukemia (CML) has been revolutionized by the discovery of tyrosine kinase inhibitors (TKIs) against BCR-ABL1 oncogenic fusion protein. Imatinib, the first BCR-ABL1 TKI, was introduced into clinical practice in the early 2000s. In the following years, the so-called second-generation TKIs (2GTKIs)-dasatinib, nilotinib, and bosutinib were approved, initially for patients resistant to imatinib, and subsequently for front-line treatment. With multiple TKIs available, selection of first-line therapy is challenging. CML risk, patient characteristics and potential toxicities of different TKIs play a fundamental role, in particular when deciding between imatinib and 2GTKIs as frontline treatment. So, when deciding front-line therapy for a patient with CML in the chronic phase (CML-CP), clinicians must consider both the long-term outcomes, such as overall survival and progression-free survival, as well as safety, tolerance and possible treatment discontinuation. This paper offers a practical algorithmic approach for the sequential use of commercially available TKIs in patients with CML-CP along with the data available in the literature.