The discovery of ETS gene fusions as common events in prostate cancer represents a significant advance in understanding of the carcinogenesis of this disease. Nevertheless, these chromosomal fusion events remain poorly understood and their functional significance and therapeutic potential remain unclear. Despite this they have been utilised as molecular handles to dissect the diversity of prostate cancers via the use of Fluorescence In-Situ Hybridization (FISH)-based “break-apart assays”. The potential clinical implications of these ETS gene fusion events are being actively explored and are discussed in this review within the context of the existing scientific and clinical climates. Examples include their possible utilities as screening tools; markers for risk stratification; predictors of responses to therapies, particularly hormonal manipulation; biomarkers to guide early phase clinical trials; and as putative therapeutic targets. Work is ongoing to address the many questions surrounding these issues in a rapidly evolving area of research. It is envisioned that an improved understanding of the biology underpinning these genetic events can impact clinical anti-cancer drug discovery and development.