Culture affects individuals’ responses to learning and instruction. It also influences the acceptance, use, and impact of e-learning environments because instructional approaches are entrenched in a context of beliefs, expectations, and values within the context of its application. Advances in e-learning are prompting a debate as to whether or not the tools and technologies are culturally neutral, inclusive, and representative. The aim of this chapter is to provide a background for understanding the links between cultural content and context and e-learning. The discussion relates instruction to technology in the face of dynamic socio-cultural issues and changing instructional systems. In doing so, challenges and exemplars from the African perspective are presented.