This chapter studies the cotton rat, Sigmodon hispidus, which is a New World rodent with a stocky, robust stature. The average adult weight of a cotton rat is between 100 and 250 gm. The name Sigmodon comes from the sigmoid enamel loops on the grinding surface of the molar. Sexual dimorphism is not prominent, but males and females can be distinguished based on the size of the genital papilla and distance from the anus. The cotton rat is distinguished from the Norway rat by its smaller size, shorter tail, and longer grizzled fur. The lifespan of the hispid cotton rat is less than 6 months in the wild but in captivity animals have a survival span up to 23 months of age. The cotton rat ( Sigmodon) species has been recognized as a significant animal model for diseases caused by a variety of human and rodent pathogens. The primary research use for cotton rats is for studies into infectious disease and immunology.