Prion protein (PrP) is a pathogeny identified in recent years, which infects both mankind and other mammals. It has been proved that PrP is a sole protein able to duplicate and propagate with itself. PrP can express in many tissues and has important physiological functions in many species of animals. The conformation change of PrP is the origin of transmissible spongiform encephalopathies (TSEs). It has been proved that the sheep genetic diversity of prion protein gene (PRNP) is significantly associated with the resistance to scrapie. In this review, the evidence of association between polymorphisms of PRNP and resistance or susceptibility to scrapie and its effects on reproduction and performance traits were focused. The aim is to provide theory guidance for sheep breeding resistant to disease.