Transferosomes are ultradeformable vesicles for transdermal applications consisting of three main components: the active substance, lipids and an edge activator. Compared to liposomes, transferosomes are able to reach intact deeper regions of the skin after topical administration delivering higher concentrations of active substances making them a successful drug delivery carrier for transdermal applications. Most transferosomes contain phosphatidylcholine (C18) as it is the most abundant lipid component of the cell membrane, and hence, it is highly tolerated for the skin, decreasing the risk of undesirable effects, such as allergies or urticaria. The most common edge activators are surfactants such as sodium deoxycholate, Tween® 80 and Span® 80. Their chain length is optimal for intercalation within the C18 phospholipid bilayer. There is a very wide variety of drugs that have been successfully encapsulated within transferosomes such as phytocompounds like sinomenine or apigenin for rheumatoid arthritis and leukaemia respectively, small hydrophobic drugs but also macromolecules like insulin.. The key factor in order to develop optimal transferosomal formulations (with high drug loading and nanometric size) is to identify the optimal ratio between the main components as well as the critical process parameters for their manufacture. Application of design of experiments (DoE) and quality by design (QbD) is crucial to understand the interplay among all these factors not only during the preparation at lab scale but also in the scale-up process. Clinical trials of a licensed ketoprofen transferosomal gel have demonstrated that were tolerable and effective. Although the product was discontinued after coming into the market due to only marginal superior efficacy to that of vehicle-free ketoprofen, these nanomedicinal formulations have reached the market. Learning from DoE and optimising transferosomal formulation is critical in ensuring quality needed for their translation and reducing manufacturing costs to ensure these products are viable compared to classical topical formulations.