Only limited data are available currently on the clinical performance of uncemented total ankle replacements. Even so, various complications, notably loosening and/or migration of the talar and/or tibial components, already have been seen. Nonetheless, the current consensus is that, in all likelihood, uncemented total ankle prostheses will continue to be implanted in some patients. Therefore, it is important that future designers of this prosthesis be conversant with all the requirements that a design must fulfill, be aware of the various features of second-generation designs that were introduced to address problems seen in implanted cemented first-generation replacement designs, be knowledgeable about the in vivo performance, to date, of uncemented second-generation total ankle replacement designs and how features of a design may impact its performance, and be cognizant of the gaps and/or controversies in the literature and the extent to which they could be addressed through focused research. All of these four aspects, which have been treated inadequately in the literature, are treated in detail in the current review, with the hope that the review will serve as a primer for those involved in designing the next generation of uncemented total ankle replacements. Thirteen design requirements, including kinematics, kinetics, and stability aspects, are described. Various features of three second-generation designs are described. For three second-generation designs, the relationship between their estimated in vivo performance and the extent of joint resurfacing needed to implant them is presented. Among the seven future research areas discussed are design, fabrication, and validation of an ankle simulator, and development of a set of standardized biomechanical tests.