Up to 70% of survivors of adult-onset, non-central nervous system (CNS) solid tumors report cognitive symptoms, and approximately 30% have impairment on formal neuropsychological testing. The etiology of the impairment is unknown. There is a lack of robust evidence on how to prevent or treat cancer-related cognitive impairment (CRCI). Here, we review the evidence for the putative mechanisms of CRCI by examining clinical and preclinical models, primarily those associated with chemotherapy. Pharmacologic and nonpharmacologic options for treating CRCI are discussed based on the best evidence available. Practical clinical advice for health professionals managing patients with CRCI is also provided.