The roles of substrate complexity (molecular size of the substrate) and process configuration in anaerobic wastewater treatment were investigated to determine optimal methanogenic technology parameters. Five substrates (glucose, propionate, butyrate, ethanol, and lactate) plus a mixed waste (60% carbohydrate, 34% protein, and 6% lipids) were studied under five reactor configurations: batch-fed single-stage continuous stirred tank reactor (CSTR), continuously fed single-stage CSTR, two-phase CSTR, two-stage CSTR, and single-stage upflow anaerobic sludge blanket (UASB). The substrate feed concentration was 20,000 mg/L as COD. The solids retention time (SRT) and hydraulic retention lime (HRT) in the CSTR reactors were 20 d, while HRT in the UASB was 2d. All reactors were operated for at least 60 d (equal to 3SRT).