Genome-scale models have expanded beyond their metabolic origins. Multiple modeling frameworks are required to combine metabolism with enzymatic networks, transcription, translation, and regulation. Mathematical programming offers a powerful set of tools for tackling these “multi-modality” models, although special attention must be paid to the connections between modeling types. This chapter reviews common methods for combining metabolic and discrete logical models into a single mathematical programming framework. Best practices, caveats, and recommendations are presented for the most commonly used software packages. Methods for troubleshooting large sets of logical rules are also discussed.