Hybridization with exfoliated two-dimensional (2D) nanosheets provides a very effective and powerful way not only to control the physicochemical properties of hybridized species but also to explore nanocomposites with novel functionalities. Deliberate coupling between the hybridized species is critically important in maximizing the effect of hybridization on the physicochemical properties and functionality of hybridized components. The very small thickness and extremely large surface of exfoliated 2D nanosheets render these materials ideal candidates for achieving a strong coupling with diverse guest species. This Perspective focuses on the unique characteristics of exfoliated 2D nanosheets as building blocks for designing hybrid materials. Several intriguing examples of strong interaction between exfoliated 2D nanosheets and hybridized species are summarized with an emphasis on the effective control of electronic, optical, structural, and morphological characteristics. An outlook on the future research directions is provided along with new strategies to maximize the coupling in the 2D nanosheet-based hybrid materials.