It is now well established that residues from therapeutic drugs consumed by humans can end up, through the sewage system, in the surface water of populated areas. Given that the global production of major illicit drugs is comparable to that of widely used pharmaceuticals, we tested for the presence of drugs of abuse (cocaine, opioids, amphetamines and cannabis derivatives), some related opioid pharmaceuticals (codeine and methadone) and/or their metabolites in Italian and British surface waters. Having identified residues of all major drugs of abuse in raw and treated urban wastewater, we now measured their levels in several rivers and lakes by a selective multi-residue assay based on liquid chromatography-tandem mass spectrometry. Recoveries in surface water were generally higher than 80%, with overall variability of the method lower than 10%. LODs were generally lower than 0.2 ng/L, and LOQs were lower than 0.6 ng/L, with few exceptions. Many of the tested substances were found in both rivers and lakes, at concentrations ranging from high pg/L to high ng/L, with loads in rivers in the range of tenths to hundreds of grams per day. Our data indicate that residues of drugs of abuse have become widespread surface water contaminants in populated areas. Since most of these residues still have potent pharmacological activities, their presence in the aquatic environment may have potential implications for human health and wildlife.