Introduction: Cancers are associated with excess cellular oxidative stress, and during cancer treatment the addition of drug-induced oxidative stress can limit the effectiveness of therapy and cause a number of side effects, such as fatigue, nausea, vomiting and diarrhea, as well as more serious adverse effects, including cardiomyopathy, peripheral neuropathy, hepatotoxicity and pulmonary fibrosis. Method: Review of the pertinent literature on oxidative stress during cancer cytotoxic therapy and the use of Molecular Replacement methods to reduce adverse effects by replacement of damaged cellular molecules. Discussion: Most of the adverse effects of cancer therapy are due to oxidative stress-mediated damage to normal tissues. For example, loss of efficiency in the electron transport chain caused by membrane peroxidation and reduction in coenzyme Q10 can occur during cytotoxic therapy using anthracyclines, alkylating agents, platinum coordination complexes, epipodophyllotoxins and camptothecins. Molecular Replacement and antioxidant administration mitigates the damage to normal tissues and reduces the adverse effects of cancer therapy without loss of therapeutic effect. Summary: The acute and chronic adverse effects of cancer chemotherapy can be reduced by Molecular Replacement. Molecular Replacement of membrane lipids and enzymatic cofactors, such as coenzyme Q10, by administering nutritional supplements with antioxidants can prevent oxidative membrane damage and reductions of cofactors in normal tissues, respectively, restoring mitochondrial and other cellular functions and reducing chemotherapy adverse effects, such as cardiotoxicity, without significantly affecting therapeutic benefit. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefit of Molecular Replacement Therapy plus antioxidants in reducing the damage to mitochondrial membranes, restoring mitochondrial electron transport function, reducing fatigue and protecting cellular structures and enzymes from oxidative damage.