Abstract: Hypertrophic cardiomyopathy (HCM) is considered a monogenic disorder primarily driven by sarcomere gene mutations; however, its significant clinical heterogeneity and the absence of clear pathogenic mutations in a substantial proportion of patients suggest a more complex mechanism. This article systematically reviews the paradigm shift in the etiology and diagnostic and therapeutic strategies of HCM from a “sarcomere disease” to an integrated systemic disease model characterized by “multigene-multicellular-multipathway” interactions. By integrating key advances across genetics, epigenetics, pathophysiology, and clinical translation, we propose that the pathogenesis of HCM is a complex process initiated by an initial genetic hit, amplified by positive feedback from the cardiac microenvironment, and modified in phenotypic severity by a polygenic background. Based on this integrated perspective, this article further analyzes the unique challenges faced when applying international cutting-edge advancements to the Chinese population and proposes actionable directions, including establishing a national precision medicine cohort, developing localized risk prediction tools, and promoting clinical research on innovative therapies. This article aims to provide Chinese internists with new insights into the diagnosis and treatment of HCM that combine theoretical depth with practical guidance.