Surface and interfacial behavior of protein molecules are crucial for the protein function involved in many bio-chemical processes and biomedical products such as enzyme design, bio-separation, drug design and delivery.This article is devoted to an overview of design and regulation of the surface and interfacial behavior of protein molecules. The improvement of enzyme surface such as the directed evolution and the rational design of enzymes is introduced at first, followed by the rational design of protein interface for the protein assembly. Thereafter, the design of micro-environment and ligands are described as two examples for the design guided by protein surface.Then the design of protein surface and interface with the help of artificial intelligence will be discussed.