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 time (HRT) in the CSTR reactors were 20 d, while HRT in the UASB was 2 d. All reactors were operated for at least 60 d (equal to 3SRT). Substrate complexity was observed to be less significant under two-phase, two-stage and UASB reactor configurations. Two-phase CSTR, two-stage CSTR, and single-stage UASB configurations yielded the lowest effluent chemical oxygen demands (130–550, 60–700, and 50–250 mg/L, respectively). The highest effluent chemical oxygen demands were detected when feeding glucose, propionate, and lactate to continuously fed single-stage CSTRs (10, 400, 9900, and 4700 mg/L COD, respectively) and to batch-fed single-stage CSTRs (11, 200, 2500, and 2700 mg/L COD, respectively). Ironically, the one stage CSTR — most commonly utilized in the field — was the worst possible reactor configuration.