Operational practice of high-rate anaerobic bioreactors such as upflow anaerobic sludge bed (UASB) reactors is generally based on maximization of the biomass concentration and, in the case of more than one reactor compartment, operation in parallel. In this article, a modeling approach is used to postulate that the treatment performance of anaerobic bioreactors can be improved by simple operational measures. To achieve minimized effluent soluble substrate concentrations, operation of two reactors in series combined with active exchange of biomass between both reactors is suggested. In this way, substrate concentrations lower than the minimum achievable concentration in a completely mixed reactor can be achieved. It is furthermore suggested that maximized biomass concentrations (and solid retention times [SRTs]) do not necessarily lead to minimized effluent concentrations of organic material. At elevated SRTs, the soluble microbial products resulting from biomass turnover are shown to represent the main fraction of soluble organic material in the effluent of the reactor, limiting treatment efficiency.