Understanding the underlying molecular mechanism of how graphene materials (GMs) interact with biological surfaces is the key to develop safe and effective biomedical applications of GMs. Here, a systematic and comprehensive mechanistic perspective of interactions between pristine GMs and biological membranes is provided. To this end, first the known mechanisms of interaction between GMs and membrane components are summarized and classified, with a focus on phospholipids, cholesterol, and membrane proteins. Both experimental observations and computational simulations are included. Detailed experimental conditions and physiochemical properties of GMs are listed for each cited application. At the end of this review, current challenges and conflicts that limit biomedical applications of GMs are discussed. Based on reported mechanisms, guidelines for future studies to address the remaining challenges are proposed, specifically with respect to modulating the intrinsic properties of GMs for more efficient and safer therapeutic applications.