As oncologics are becoming increasingly targeted, complex, and employed in combination therapies, the potential treatment and funding pathways in large and influential markets, such as the US and the UK, are undergoing fundamental transformation. Indications show that these changes may soon be reflected in many other countries. What do these changes mean for patients, physicians, payers, and manufacturers? How can manufacturers build a sustainable value message in this environment and pursue the most appropriate and cost-effective evidence generation strategies? While the US and UK currently have fundamentally different models for health care funding, the countries both face rising costs, budget constraints, and physician-led concerns about the sustainability of current care and reimbursement paradigms. In the US, a number of emerging framework, such as those from the American Society of Clinical Oncology, Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Networks offer pathways, to physicians and patients, to estimate the value of individual therapies in head-to-head comparisons. In the UK, NICE will now assess all new cancer drugs prior to marketing authorization and provide final recommendations within 90 days of market launch. In addition to the routine “recommend” and “not recommend” options, NICE may give a conditional recommendation to allow marketing of drugs which appear promising, yet have limited or insufficient evidence at the time. Drugs with conditional authorization will be funded for an interim period by the Cancer Drugs Fund. As further data are collected, there needs to be a realistic prospect of passing NICE’s cost-effectiveness threshold. Failure to gain NICE’s recommendation after the interim funding period will result in re-payment of the conditional authorization period. In this symposium, we will present the key factors to address as treatment and payment pathways change globally. The potential impact of these changes on evidence generation strategies, particularly strategies outside of randomized clinical trials, will be discussed.