The anterior cruciate ligament (ACL) serves as one of the main knee stabilizers and is commonly injured during contact and non-contact athletic activities. While extensive research on the biomechanics and treatment of ACL injuries has been conducted, one often overlooked question is the genetic component of ACL injury and whether this can contribute to diagnosis and treatment. While we have certainly made incredible strides in understanding patterns of injury and the importance of restoring knee stability with the ACL, many clinicians and researchers are still faced with the question of “Who is most at risk for an ACL injury, and why are certain groups of people more at risk than others?” To truly address this, we must adopt a broader perspective, examining ACL injuries through a population and epidemiologic lens, an approach not often taken in the literature. The purpose of this chapter is to summarize the existing literature on the genetic basis of ACL injuries based on a series of factors including sex, biomechanics, genetic markers, and heritability. Lastly, we will discuss the implication of these factors on how ACL injuries should be approached and how an understanding of the genetics may influence diagnosis and management strategies.