Stroke is a common disease with high incidence worldwide. Ischemic stroke (IS) is a major subtype of stroke. IS, a complex polygenic disease, is affected by a variety of environmental and genetic factors. Therefore, understanding the genetic risk factors for IS is an important step to clarify the pathogenesis, optimize the prevention strategy and determine new therapeutic targets of IS. Two genome wide association studies (GWASs) in 2012 and 2015 showed that there were risk loci on chromosome 6p21.1 associated with IS, but the results of subsequent replication studies were controversial. Moreover, the exploration of biological function and molecular mechanism of genetic variants on chromosome 6p21.1 affecting IS susceptibility is in the initial stage. This paper reviews the studies on the correlation between genetic variation in chromosome 6P21.1 region and IS susceptibility, in order to further clarify its mechanism in IS and provide theoretical basis for prevention and treatment of IS.