Curative therapy for metastatic disease in solid malignancies remains frustratingly elusive due to the long recognized problem of tumor cell heterogeneity and emergence of treatment resistant lesions. Cancer is a complex adaptive system. Tumor progression reflects the co-evolutionary dynamics of host-tumor interactions and the progressive selection of tumor clones of increasing fitness able to survive in varied host tissue microenvironments and to circumvent host defenses and therapeutic intervention. Improved success in confronting this intrinsic biological complexity requires major changes in current approaches to the discovery and clinical validation of new therapeutics. The following needs must be accorded higher priority. *new tools to map the dynamic topology of perturbed molecular signaling networks in malignancies arising in different cell lineages to better predict the compensatory pathways most likely to confer resistance to guide new drug development and as companion diagnostics for monitoring emergence of resistance *new approaches for therapeutic action at multiple targets in perturbed signaling networks via new combinations of targeted therapies or, more challenging, the design of promiscuous polypharmacology in a single agent *new minimally invasive blood-based diagnostics such as CTCs, ctDNA or exosomes for faster detection of resistance and agile changes in treatment regimens *new adaptive clinical trial protocols such as I-SPY for simultaneous evaluation of multiple agents and agile switching of agent combinations guided by biomarker profiling of response/resistance patterns. This will also require new regulatory paradigms to accommodate the increased statistical and logistical complexities of adaptive clinical trials and efficacy assessment of combinations of investigational agents and companion biomarkers *new value propositions for payors (and patients) linking reimbursement and pricing policies to more substantial improvements in clinical outcomes *new approaches for rapid updating of standard-of-care (SOC) guidelines and improved physician education to reflect advances in molecular oncology and greater adoption of routine molecular profiling of patients for improved therapy selection *new patient advocacy approaches to enhance patient education about the value of molecular profiling in treatment choice and increase the enrollment of eligible patients into investigational trials