The availability of multiple carbon/energy sources, as is common in wastewater treatment plants, often enhances the biodegradation of recalcitrant compounds. In this paper, we classify and model different modes of multiple substrate utilization in a systematic way, using the concept of synthesizing unit. According to this concept, substrates can be substitutable or complementary; their uptake (or processing) can be sequential or parallel. We show how the different modes of multiple substrate interaction can be described by a single general model. From the general model, we derive simple expressions for co-metabolism of substrates that are not structurally analogous. Both the general and the specific co-metabolism model have the advantage that they can be used in combination with any microbial growth model. To test the co-metabolism model's realism, we confront it with experimental data. The results attained with the co-metabolism model support that the general model constitutes a useful framework for modeling aspects of multiple substrate utilization. © 2003 Elsevier Ltd. All rights reserved.