Real-world evidence (RWE) obtained from an analysis of real-world data (RWD) is a valuable tool that can be used to aid healthcare decision-making. RWD could be derived prospectively or retrospectively from multiple sources, including electronic health records, claims databases, pragmatic trials, or registries, but they may also be gathered from patient-generated sources such as smartphones, wearable devices, and survey data. RWD supplement clinical trial data, which are usually obtained from randomized controlled trials (RCTs). However, RCTs include highly selective patient populations in tightly controlled experimental settings. While evidence obtained from RCTs is considered most reliable, the study populations may not be representative of real-world patients and the study logistics may not be representative of routine clinical practice. RWE has several applications in the United States (US). Besides aiding the pharmaceutical industry with drug development pathways and the US Food and Drug Administration (FDA) with regulatory approval decisions and safety monitoring, RWE is also used by public and private payers while making health technology assessments and payer coverage decisions, initially and during reassessment. Initially, claims-based epidemiological data can be used to identify the patient population(s) that may be eligible for a drug and to determine preliminary cost estimates. During reassessments, RWE can help guide decisions governing reconsiderati on of coverage, discounts, and formulary tiering based on efectiveness and safety observed during real-world drug use. Here, we discuss the value of RWE from a payer’s perspective, highlight the applications of RWE to payers, and illustrate how RWE has been or might be used to address gaps in evidence using clinical examples across therapeutic areas.