Polyamines are a kind of aliphatic amines that exist widely in nearly all organisms. Polyamines interact with biological macromolecules through ionic interactions and hydrogen bonds, thereby they could affect the cell growth via regulating the function of macro-molecules. The impact of polyamines on nucleic acids has been thoroughly studied. However, their effects on protein structure and functions are not well established. This review summarizes the recent progress on how polyamines affect proteins, including metabolic enzymes, ion channel proteins and other important proteins. The interaction between polyamines and proteins is discussed, and the review also summarizes the challenges in studying polyamine-protein interaction as well as the potential application of these studies on the therapy of correlated diseases.