E-learning systems cross national borders, are used by people in different cultures, and are applied in culturally different contexts. A number of factors highlight the need to be acutely aware of the role of culture as part of the whole e-learning environment. In mainstream systems development, effective strategies that address cultural issues in both the product and the process of development now often are critical to systems success. In relation to the product of development, cultural differences in signs, meanings, actions, conventions, norms or values, etc., raise new research issues ranging from technical usability to methodological and ethical issues of culture in information systems. In relation to the process of development, cultural differences affect the manner in which users are able to participate in design and to act as subjects in evaluation studies. This chapter provides a summary of the main issues within cross-cultural usability with an emphasis on web-based systems. It discusses the application of generic models and theories to the field of e-learning systems and provides an agenda for future research required to ensure usability in international web-based e-learning systems.