A European Consensus on the management of prostate-specific antigen (PSA) relapse in patients with prostate cancer has been formulated. The key recommendations proposed are that total PSA is the best detection tool for prostate cancer, with free and complexed PSA having a role in the PSA range 1–4 ng/ml. PSA relapse after radical prostatectomy (RP) has been defined as a value of 0.2 ng/ml with one subsequent rise, while the ASTRO definition should be used after radiotherapy. A PSA level of less than 0.4 ng/ml after hormonal therapy can be considered an indicator of a positive response. Continuous assessment using nomograms or artificial neural networks will help to determine whether progression after local therapy is distant or local, which is the basis for treatment decisions. Secondary treatment after local failure of RP should be initiated when PSA levels reach 1.0–1.5 ng/ml and salvage radiotherapy can be considered with or without hormonal therapy. Local failure after radiotherapy can be treated with a choice of high-intensity-focused ultrasound, salvage RP (only in highly selected patients), cryotherapy or external beam radiation. Treatment of distant failure involves hormonal manipulation, the type and the timing of which is based on both physician and patient preferences.