Molecular diversity is a hallmark of life. Unfortunately, given that the clinical benefit of a drug can only be realized under certain genetic/molecular conditions, such heterogeneity can mean the difference between survival and death. For most targeted therapies it appears that such conditions are met in only a small percentage of patients, particularly in the monotherapy context. Notwithstanding, the nonresponder phenomenon can be viewed as a low-hanging fruit among medical needs, with a large body of scientific knowledge surrounding the target and the diseased system. This knowledge, together with information about the molecular sources of nonresponse, provides a rational framework upon which novel intervention strategies can be built. Driven by such molecular considerations and the enormous economic implications, new levels of innovation are urgently required. Systems level patient characterization coupled with innovative in silico strategies hold great promise and suggest a future of theranostic-linked combination therapies, optimized cohort selection and rational prioritization of clinical opportunities.