The past decade has witnessed great advances in the treatment of chronic myeloid leukemia (CML), brought about in large part by the development of BCR-ABL tyrosine kinase inhibitors (TKIs). Bosutinib joins the armamentarium of approved TKIs for the treatment of chronic phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome (Ph)-positive CML resistant to or intolerant of prior therapy. Bosutinib has an adverse-event (AE) profile distinct from that of other TKIs. Diarrhea is the predominant toxicity associated with bosutinib treatment; other commonly reported nonhematologic AEs include rash and liver enzyme elevations. Cardiac events, fluid retention, and electrolyte abnormalities are infrequent. Optimal response to bosutinib requires adherence, which depends, in part, upon optimal management of associated toxicities. The oncology clinician can facilitate this process by providing patient education, timely patient follow-up, and close monitoring to promptly identify and manage AEs. Thus, optimal patient management requires a thorough and current understanding of toxicity profiles and AE management paradigms. This review provides an overview of bosutinib safety data derived from ongoing clinical trials and offers practical clinical strategies currently used to manage toxicities associated with bosutinib treatment in patients with Ph-positive CP, AP, and BP CML.