Interest in the development of graphene-based materials for advanced applications is growing, because of the unique features of such nanomaterials and, above all, of their outstanding versatility, which enables several functionalization pathways that lead to materials with extremely tunable properties and architectures. This review is focused on the careful examination of relationships between synthetic approaches currently used to derivatize graphene, main properties achieved, and target applications proposed. Use of functionalized graphene nanomaterials in six engineering areas (materials with enhanced mechanical and thermal performance, energy, sensors, biomedical, water treatment, and catalysis) was critically reviewed, pointing out the latest advances and potential challenges associated with the application of such materials, with a major focus on the effect that the physicochemical features imparted by functionalization routes exert on the achievement of ultimate properties capable of satisfying or even improving the current demand in each field. Finally, current limitations in terms of basic scientific knowledge and nanotechnology were highlighted, along with the potential future directions towards the full exploitation of such fascinating nanomaterials.