Atherosclerosis (AS) manifested by lipid accumulation, extracellular matrix protein deposition, and calcification in the intima and media of the large to medium size arteries promoting arterial stiffness and reduction of elasticity. It has been accepted that AS leads to increased morbidity and mortality worldwide. Recent studies indicated that genetic abnormalities play an important role in the development of AS. Specific genetic mutation and histone modification have been found to induce AS formation. Furthermore, specific RNAs such as microRNAs and circular RNAs have been identified to play a crucial role in the progression of AS. Nevertheless, the mechanisms by which genetic mutation, DNA and histone modification, microRNAs and circular RNA induce AS still remain elusive. This review describes specific mechanisms and pathways through which genetic mutation, DNA and histone modification, microRNAs and circular RNA instigate AS. This review further provides a therapeutic strategic direction for the treatment of AS targeting genetic mechanisms.