Abstract There is no specific regulatory definition of drug resistance. However, regulatory considerations relevant to strategies designed to address drug resistance can be described based on a number of factors. One way to consider the topic is whether a particular strategy is designed to overcome resistance that has already developed (presumably with clinical manifestations) or whether the strategy under consideration is designed to prevent drug resistance from occurring. An approach that has the promise of providing therapies that could play a role in preventing or overcoming drug resistance is combining two or more experimental treatments early in development with the intent of registration of two or more novel agents combined for the treatment of a particular patient population. Recent guidance and public discussion from FDA officials indicates an understanding of the need for continued evolution of thinking around trials with registration intent. Notably, the FDA has indicated a willingness to consider trial designs where two novel agents A and B could be used together in a randomized trial in comparison with a control regimen without the need to isolate the contribution of each agent in the phase 3 setting. Depending on the biology of the tumor in question and the mechanism of action of each agent, such a strategy may fall into the category of treatment of resistance, prevention of resistance, or both. Another clinical strategy often cited is a “maintenance” approach, where an agent used for initial treatment and disease eradication/control either alone or with other agents can be subsequently continued for a longer duration in order to reduce the risk of recurrence or progression. Such a strategy has an important role to play. However, it can be challenging to design trials that specifically address such an approach. For example, regulatory agencies often express a preference for a second randomization, a design feature that is challenging in terms of sample size and other design elements. In the U.S., the accelerated approval mechanism outlined by Subpart H and Subpart E regulations provides an opportunity for development and registration in areas of unmet need. Although the regulations do not refer specifically to drug resistance, clearly patients with advanced malignancies who are at risk for or who have developed resistance do represent an area of unmet need. However, the experience with accelerated approval in oncology, if looked at from the perspective of drug resistance, may be viewed as one where most strategies have relied on evaluating novel therapies in situations where resistance has already resulted in clinical manifestations, often multiple times, as many of the patient populations evaluated have demonstrated progression after multiple therapies. Here, the recent advances in biology such as in detection of residual disease through molecular techniques may offer an evolution of this paradigm without the need for any change in existing regulation. Taking the HIV experience as one model where CD4 counts and HIV viral load changes at 24 weeks have served as the basis for accelerated approval with confirmation of benefit with data at 48 weeks, one could envision a situation in oncology where effects on a pathway relevant to development of resistance to standard treatment could be the basis of a subpart H approval in a randomized trial with confirmation of benefit with longer follow up looking at overall survival or progression free survival. In summary, although there is not one definition or mechanism to address resistance from a regulatory perspective, there are existing mechanisms that can be currently used and even further leveraged. Examples include FDA's recent guidance on novel combinations, the accelerated approval mechanism that has been in place for two decades in the US, and recent advances in biology and a more precise evaluation of pathways that are central to disease pathogenesis and resistance to therapy that can be used in the evolution of regulatory science.