Graphene is expected to revolutionize several application areas ranging from portable energy conversion and storage to miniaturized biosensors for medical applications. In this endeavor, the control of surface characteristics is an essential aspect for understanding fundamental phenomena occurring at the graphene‐liquid interface. In this comprehensive review, we address recent progress in the investigation of the interfacial characteristics of monolayer graphene and methods for modulating the physical and chemical properties of this interface. We focus on the electrochemistry and field‐effect measurements in liquid, which provide an improved understanding of the unique graphene‐liquid interface, with due consideration of the influence of the underlying substrate and structural defects in graphene. Finally, we present reported examples of using single graphene monolayers in miniaturized devices for realizing sensors, neural interfaces and batteries.