GPR56 is a relatively recent addition to the adhesion-GPCR family. Genetic and biochemical studies uncovered its roles in cancer and development and established its function as an adhesion receptor to mediate the interactions between cells and extracellular matrix. Despite of much progress on understanding its biological implications, the mechanism of its function remains elusive. It has not been firmly established whether GPR56 signals directly through G proteins and what its upstream stimuli and downstream effectors are to execute its various biological effects. This chapter will give an overview of the primary structures of the Gpr56 gene and its encoded protein and attempt to point out open questions in this research area, with an emphasis on its roles in cancer and signal transduction.