The development of genomic technologies has ushered in the era of pharmacogenomics. However, discoveries and clinical use of targeted therapies are still in their infancy. A focus on monogenic pharmacogenetic traits may contribute to this lack of progress. Variation in drug response is likely a complex paradigm involving not only genomic factors but proteomic, metabolomic and epigenomic influences. The incorporation of these omics elements into pharmaceutical development and clinical decision-making will ultimately require the use of methods to determine clinical and economic value. Current methodologies and guidelines for determining clinical effectiveness and cost-effectiveness may have limited applicability to the increasingly personalized nature of omics treatment strategies. Using examples from oncology, this article argues for the adaptation and tailoring of three existing methods for ensuring development and clinical use of multiomics-guided therapies that are effective, safe and offer value for money.