Research on literacy has become universal and is essential for researchers of various disciplines, educators, and psychologists. For this article, we examined the most important methodological challenges that arise when conducting literacy research across languages, some of which have long been acknowledged in the relevant literature. Specifically, we focused on challenges related to research on word reading, spelling, passage comprehension, and writing, ranging from the target skills, constructs, and assessment issues to the matching of the samples and measurement and factorial invariance issues. We conclude that although theoretical and applied issues have been addressed in the literature, to date, this has happened only with limited relevance for reading and writing research across languages. The discussion provides some relevant evidence from a neuroscience perspective to promote useful insights and greater methodological rigor in literacy research across languages.