Chicken heterophils are major components of the innate immune system and constitute the first guard of defence against invading microorganisms. Heterophils in contrast to mammalian neutrophils, lack myeloperoxidase, an essential enzyme of oxidative antimicrobial activity and their antimicrobial activity depends mainly on the non–oxidative mechanism. Heterophils are equipped with very efficient non–oxidative mechanism against microorganisms where the cationic antimicrobial peptides are the most powerful molecules of this killing activity with their broad spectrum activity and the ability to kill microorganisms even with very small concentrations may constitute a new antibiotic class and the basis for new feed additives. These polymorphonuclar cells are the best model for killing activity based on oxygen independent mechanisms. Disorders in the non-oxidative antimicrobial activity induced either by genetic mutations or immunomodulation diseases have direct effect on the killing capacity of heterophils. This review focuses on the heterophils main activity, cationic antimicrobial peptides isolated from chicken heterophils with their remarkable antimicrobial activity and the protective effect of heterophils in different states.