Recently, data from two randomized phase III studies that compared docetaxel-based chemotherapy to mitoxantrone-based therapy demonstrated that treatment with docetaxel can prolong life in a significant way for patients with hormone-refractory prostate cancer. For many patients who experience disease progression after androgen-deprivation therapy, however, chemotherapy may not be immediately indicated. Such cases include those individuals with hormone-refractory disease in the absence of clinical metastases, and those with asymptomatic metastatic disease, for example. As a result, clinicians treating patients with hormone-refractory disease must weigh the benefits of earlier chemotherapy against its risks, and may consider other therapies such as secondary hormonal approaches before initiating chemotherapy. This decision is further complicated by the fact that a phase III study designed to compare secondary hormonal therapy with chemotherapy has failed due to lack of accrual. Furthermore, the limitations of chemotherapy for prostate cancer are being clarified and include a lack of standard second-line therapy as well as uncertain benefits for those with non-metastatic disease. In this review, we will highlight some of the issues that impact on the decision of when to start chemotherapy and in whom as well as the potential benefits of secondary hormonal approaches.