Drug delivery and delivery systems are among the most important research disciplines today, and the relevance of nanofibers in achieving the appropriate release profile at specified sites for increased therapeutic advantages cannot be understated. Nanofiber-based drug delivery systems are fabricated and modified using a range of methods that entail a variety of factors and processes; tuning of these allows control of the drug release such as targeted, extended, multistage, and stimuli-responsive release. We explore nanofiber-based drug delivery systems from the most recent accessible literature, focusing on materials, techniques, modifications, drug release, applications, and challenges. This review offers a thorough assessment of the current and future potential of nanofiber-based drug delivery systems, with a particular emphasis on their capabilities in stimuli-responsive and dual drug delivery. The review begins with an introduction to the important characteristics of nanofibers that are useful in drug delivery applications, followed by materials and synthesis procedures for various types of nanofibers, as well as their practicality and scalability. The review then focuses on and explores the modification and functionalization strategies of nanofibers as essential features for regulating the applications of nanofibers in drug loading, transport, and release. Finally, this review investigates the range of nanofiber-based drug delivery systems in satisfying the current requirements by pointing out the areas that need improvement, followed by critical analysis, and offers probable solutions. © 2023 American Chemical Society.