We present an isotopic-dilution direct injection reversed-phase liquid chromatography-tandem mass spectrometry method for the simultaneous determination of 23 drugs of abuse, drug metabolites, and human-use markers in municipal wastewater. The method places particular emphasis on cocaine; it includes 11 of its metabolites to facilitate assessment of routes of administration and to enhance the accuracy of estimates of cocaine consumption. Four opioids (6-acetylmorphine, morphine, hydrocodone, and oxycodone) are also included, along with five phenylamine drugs (amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine, methylbenzodioxolyl-butanamine, and 3,4-methylenedioxy-N-ethylamphetamine) and two human-use markers (cotinine and creatinine). The method is sufficiently sensitive to directly quantify (without preconcentration) 18 analytes in wastewater at concentrations less than 50 ng/L. We also present a modified version of this method that incorporates solid-phase extraction to further enhance sensitivity. The method includes a confirmatory LC separation (selected by evaluating 13 unique chromatographic phases) that has been evaluated using National Institute of Standards and Technology Standard Reference Material 1511 Multi-Drugs of Abuse in Freeze-Dried Urine. Seven analytes (ecgonine methyl ester, ecgonine ethyl ester, anhydroecgonine methyl ester, m-hydroxybenzoylecgonine, p-hydroxybenzoyl-ecgonine, ecgonine, and anhydroecgonine) were detected for the first time in a wastewater sample.