The Ribonuclease-4 (RNase-4) is one member of the ribonuclease A superfamily. RNase-4 displays the highest level of inter-species sequence similarity (approximately 90%) among the whole family, and unique uridine-specificity enzymatic properties, which relates to its three-dimensional (3D) structure. The biological functions of RNase-4 have not been well characterized to documents, although it is possibly associated with host defence by degrading polymeric RNA released from specific pathogens. Recently studies have revealed that RNase-4 protects neuron degeneration diseases through promoting angiogenesis, neurogenesis, and neuronal survival under stress in neurodegeneration diseases. This review summarizes the molecular characterization, three-dimensional structure, enzymatic properties, and biological functions of RNase-4, and gives fresh perspectives on further investigation and clinical application of RNase-4.