Nuclear-cytoplasmic shuttling is a highly regulated and complex process, which involves both proteins and nucleic acids. Changes in cellular compartmentalization of various proteins, including oncogenes and tumor suppressors, affect cellular behavior, promoting or inhibiting proliferation, apoptosis and sensitivity to therapies. In this review, we will recapitulate the role of various shuttling components in Chronic Myeloid Leukemia and we will provide insights on the potential role of shuttling proteins as therapeutic targets.