High-dose chemotherapy with blood progenitor cell transplantation is increasingly recognized as a potentially valuable treatment for breast cancer, germ cell cancer, ovarian cancer and other solid tumors. A variety of cytotoxic drugs, particularly alkylating agents, have been investigated either alone or in combinations. Current, predominantly small, phase I and phase II clinical trials to not adequately compare the efficacy of these regiments and patterns of dose-limiting extramedullary toxicity are emerging. Busulfan, carmustine (BCNU) and mitomycin C cause veno-occlusive disease (VOD) of the liver in some patients and the latter two agents also cause interstitial pneumonitis. Cisplatin and ifosfamide only allow minor dose escalation before renal failure becomes prohibitive. Cyclophosphamide, thiotepa, melphalan and etoposide allow substantial dose escalation above standard and are mainly associated with mucositis. Moderate dose escalations of mitoxantrone and carboplatin are possible, limited by cardiotoxicity and neurotoxicity, respectively. Advances in supportive care have abolished bone marrow suppression as the dose-limiting toxicity in chemotherapy. Severe and potentially fatal extramedullary toxicity following high-dose chemotherapy can only be avoided by administering agents with predictable toxicity patterns and by carefully considering their clinical pharmacology.