Colorectal cancer has become the third most common cancer in the world. Early diagnosis and treatment can significantly reduce colorectal cancer mortality. The current routinely used fecal-based screening methods do not provide satisfactory sensitivity. Although colonoscopy provides macroscopic diagnosis, the compliance is low due to its inconvenience and complications. Hence, the development of new screening methods is needed urgently. Peripheral blood SEPT9 gene methylation assay has become a potential option with promising future for early detection and screening of colorectal cancer. It is shown to be convenient, reliable with good compliance by several clinical trials. This article will review the theoretical foundation and development of the assay, focusing on its clinical trials, comparing it with other screening methods and discussing its future applications.