Abstract Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels, and represent the leading cause of death worldwide, taking more lives than all forms of cancer combined. An estimated ~18 million people die from CVDs annually, representing 31% of all global deaths, making it a leading cause of death for both men and women. Clinical studies have revealed significant disparities between women and men in the incidence of, and mortality from, CVDs. CVDs develops 7 to 10 years later in women than in men but is still the major cause of death in women. Since 1984, overall mortality from CVDs has remained higher in women than men. For far too long, cardiovascular disease was considered a “man’s illness”, and women have been under-represented for years as subjects in all phases of cardiovascular research, from basic science to clinical application. Because men and women are biologically and physiologically distinct, often suffer differently from the same diseases, and respond differently to the drugs, there is an urgent need for improvement in the current preventive, diagnostic, and treatment strategies by considering sex-specific differences in the etiology and risk factors of CVDs. As an example, recent advances in organ-on-a-chip platforms have enabled the recapitulation of both physiological and pathological conditions of complex tissues and organs in vitro, including those of the heart. However, none of these models ever truly considered sex as an important biological variable. The goal of this bold new methods R21 project is to reveal sex differences in an engineered microfluidic cardiac hypertrophy-on-a-chip platform, populated with sex-specific cardiac cells. It is hypothesized that there exist critical differences between sexes in the development of biomechanically induced and/or biochemically induced cardiac hypertrophy in the biomimetic on-chip platform. Sex as an important biological variable in heart-on-a-chip systems has not been investigated so far and we envision our high-risk, high-reward project to lay down the basis for future in-depth investigations on this indispensable but highly underrepresented parameter.