Future strategy for drug combination predictions with parallel integration of computational modeling, preclinical testing, and clinical trials. A) Future combinatorial drug discovery approaches will benefit from tighter integration of gene signatures and phenotypic screen data with computational models, tuning the models to specific cancer cell-lines. Model simulations enable prediction of effective drug combinations for preclinical validation. Preclinical data can then be used to further refine computational models. B) For clinical application, patient gene signatures can be clustered with gene expression signatures from previously modeled cell lines. Similarity scores can then be computed to find the most similar model to the patient’s tumor for selection of the appropriate drug combination.