Saccharomyces cerevisiae (S. cerevisiae) was the first eukaryote to have its full genome sequenced, which makes it one of the longest studied genomes. The scientific community has established that S. cerevisiae is a useful model in the study of human diseases due to the homology that exists in numerous human and yeast genes. Yeast artificial chromosomes (YACs) have been developed that contain inserts of human DNA. These YACs can be used to study the mechanisms that cause DNA fragility in humans by placing a known human fragile site within a YAC. Though it is useful to study human DNA inserted into yeast to monitor the inherent fragility of the sequence, studying the nature of native yeast fragile sites may have benefits as well. The types of native fragile sites in Saccharomyces cerevisiae include Mec1 mutant, hydroxyurea, palindromic, ty-element, and Pol1 mutant induced fragile sites. Many of the mechanisms of yeast DNA fragility are similar to those of human DNA. The purpose of this review is to compare and contrast the mechanisms of fragility in S. cerevisiae and human DNA. Though human and yeast fragile sites are not always caused by similar means, with further study of the native fragile sites in S. cerevisiae, more similarities may be found that can give further insight into the human fragile sites and diseases caused by them.