For several decades, androgen deprivation (AD) has been the mainstay for treating metastatic prostate cancer. AD can be attained by a variety of means; however, irrespective of modality and a gratifying initial high response rate, almost all patients advance to a state of androgen independence and ultimately a hormone-refractory state. Improved understanding of the biology and mechanisms of progression to androgen independence coupled with promising preclinical data have led to investigating intermittent AD (IAD) as a way of improving disease control while maintaining quality of life. Preliminary published clinical experience, mostly from uncontrolled trials, suggests the feasibility of this approach. Two ongoing cooperative-group phase III trials are evaluating the survival impact of IAD both in patients with metastatic disease and in those with prostate-specific antigen failure post-radiation therapy. There are several unanswered questions regarding this approach, and until more definitive data regarding its safety and impact on survival are available, IAD should be considered experimental. In this review, we detail the background and preclinical scientific rational for investigating IAD, and we review published clinical experience and describe the ongoing phase III clinical trials. We also discuss special considerations for using IAD outside the context of a clinical trial.