There is now substantial evidence for a role for cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) signalling during carcinogenesis in a number of tissues and selective COX-2 inhibitors (coxibs) were considered attractive candidate chemoprevention agents. However, recent concerns over the toxicity of systemic selective COX-2 inhibition and the realisation that COX-1 may also contribute to carcinogenesis have cast some doubt on COX-2 inhibition as a safe and effective chemoprevention strategy. This review will describe the available evidence relating to the known benefits (preventive efficacy in rodent tumorigenesis models and limited human data from small randomised, controlled trials and epidemiological studies) and risks (cardiovascular and renal toxicity) of coxib therapy for cancer chemoprevention. Potential, alternative strategies for inhibition of COX-PG signalling that minimise or avoid systemic selective COX-2 inhibition will also be discussed.