Patients with castration-resistant prostate cancer (CRPC) who show progression of disease after first-line chemotherapy with docetaxel have few proven treatment options. Mitoxantrone plus prednisone is frequently used in this setting. The retrospective analysis by Berthold et al. of mitoxantrone after first-line docetaxel in patients with CRPC suggests that mitoxantrone has a modest level of activity in this setting, with a second-line PSA response rate of 15% and a median time to PSA progression of 3.2 months. Patients with CRPC treated with docetaxel after progression on first-line mitoxantrone had a PSA response rate of 28% and a median time to PSA progression of 5.9 months. In this analysis, median survival of patients was 10 months and did not differ according to choice of first-line agent. Mitoxantrone therapy can be considered in select patients after failure of first-line docetaxel, and vice versa. Other cytotoxic agents such as carboplatin might have a limited role in this patient population. In general, patients with CRPC should be directed towards clinical trials, when available.