Defined by the presence of four or more repeating units containing a conserved core of approximately 40 amino acids that usually ending with tryptophan-aspartic acid (WD), WD-repeat proteins belong to a large and fast-expanding conservative protein family. As demonstrated by the crystal structure of the G protein beta subunit, all WD-repeat proteins are speculated to form a circularized beta propeller structure. The importance of these proteins is not only demonstrated by their critical roles in many essential biological functions ranging from signal transduction, transcription regulation, to apoptosis, but is also recognized by their association with several human diseases. Defining the function of a WD-repeat protein is the current challenge. It is, however, paramount to uncover the function of individual WD-repeat proteins, explore the protein interaction mechanism through WD-repeat domains and, ultimately, understand the complex biological processes and organisms themselves.