<p>Transdermal delivery systems (TDDS) mark a revolutionary concept in contemporary pharmacological treatments, providing an efficient replacement for the classical methods of drug administration through the oral route and other parenteral routes of administration, bypassing the first-pass effect and ensuring better patient compliance. Nevertheless, the topical delivery of drugs often becomes an issue due to the role played by the <i>stratum corneum</i>, which acts as the primary resistance point on the skin. For this purpose, ethosome-based nanoparticles have been recognized as a highly flexible carrier system. In contrast to liposomes, ethosomes exhibit a high content of ethanol (20–45%) that helps fluidize the bilayer structure of lipids present in the skin and facilitate transdermal permeation of drugs. This review offers an in-depth insight into the various designs of ethosome carriers and provides a detailed classification of the systems into Classical, Binary, and Transethosomes. The manuscript makes a thorough comparison among the systems based on their structural differences, their respective modes of penetration, and relative strengths in terms of drug loading and physicochemical stability. Moreover, the complexities involved in their preparation are illustrated, particularly the importance of the stirrer speed, typically between 700 and 1200 RPM, and other parameters, including temperature maintenance and lipid: ethanol ratios, that determine the size and distribution of the vesicles formed. Alongside formulation approaches, the potential of ethosomes as a therapy against various skin diseases like psoriasis, acne, and fungal infections is highlighted, in addition to the application in systemic vaccinations. Importantly, this review addresses the issues associated with the implementation of the technology in clinical settings, especially concerning shelf-life stability of the preparations, cutaneous irritation due to ethanol, and the absence of international regulations for topical nanosystems. Through integration of relevant research conducted up until 2024 and 2025, the review forms the basis for next-generation ethosomes.</p> Graphical Abstract <p></p>