Abstract: Printed or digital text is a primary communication medium. Reading is necessary for locating, understanding, and using information in our personal and professional lives. The importance of reading makes typography essential to accessibility. The purpose of this systematic literature review was to examine design factors that influence the legibility and readability of accessible typography, resulting in 42 peer-reviewed empirical studies (2000–2025) that report on typeface design, typesetting, and other factors affecting legibility and readability of typography in Latin alphabet-based languages. Key findings include: (1) serifs are not a significant legibility factor; (2) no single type size or typeface optimizes readability for everyone in every situation; and (3) familiarity may be a significant legibility and readability factor. These results suggest that accessible typography guidelines should reflect the complexity and nuance involved in optimizing readability and identify several research gaps. Future research should explore typeface design characteristics beyond serifs within type classifications, the influence of familiarity on readability and reading skills, the potential transferability of familiarity between similar typefaces, the duration of the familiarization process, the persistence of its effects, and whether reader motivation and adaptability can outweigh these effects. Additionally, accessible typography research may benefit from studies incorporating natural reading conditions, materials that better reflect current design practices, more diverse reading measures, and in-depth qualitative approaches.