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Substantial progress has been made in understanding the genetic basis of HSCR with the help of advanced genetic analysis techniques and animal models. More than 11 genes have been found to be involved in the pathogenesis of HSCR. The <jats:italic>RET<\/jats:italic> gene is the most important susceptibility gene involved in HSCR with both coding and non\u2010 coding sequence mutations. Due to phenotypic diversity and genetic complexity observed in HSCR, mutational analysis has limited practical value in genetic counseling and clinical practice. In this review, we discuss the progress that has been made in understanding the molecular genetics of HSCR and summarize the currently identified genes as well as interactions between pathways and gene\u2010modifying loci in HSCR. 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