The removal of approved drugs from the clinical market, as well as late-stage failures in clinical trials, are often linked to unforeseen cardiac toxicity. To address this problem, independent organizations including the food and drug administration (FDA), pharmaceutical companies, contract research organizations, and academic institutions are evaluating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a complementary tool for the toxicity and safety assessment of novel therapeutic compounds. hiPSC-CMs are an integral component of a new paradigm, the Comprehensive in vitro Proarrhythmia Assay (CiPA) Initiative, through which panels of compounds with known mechanism of cardiotoxicity are being evaluated in hiPSC-CM platforms across independent test sites and using a number of novel cutting-edge technologies. Three key challenges under consideration for this cellular system are sub-ideal cardiomyocyte geometry, sub-cellular structural organization, and overall electro-physiological maturity. Alternative bioengineering and electrical stimulation approaches developed to enhance hiPSC-CM maturity have shown improvements in aspects of hiPSC-CM physiology, however those approaches have limited scalability and thus are not amenable to high throughput screening. The StemoniX microHeart technology comprises a physiologically-relevant high throughput screening platform that passively promotes cardiomyocyte alignment. hiPSC-CMs cultured in microHeart display more physiological cellular geometry, coherent unidirectional contraction, cardiac cell junction and nuclear re-modeling, enhanced expression of key cardiac physiology genes, and improved calcium handling. Thus, the microHeart platform enables high throughput screening of hiPSC-CMs that displaying more physiologically-relevant features. To evaluate whether the changes induced by the microHeart alignment system translated into differential responses to cardio-active compounds, high throughput calcium flux assays were performed on hiPSC-CMs cultured in standard high throughput screening cell cultureware or microHeart 384-well plates and subsequently interrogated with compounds included in the CiPA initiative. Differential responses were observed in nearly 60% of the compounds tested, indicating that the cellular changes induced by microHeart alignment have important consequences to cardiomyocyte physiology, which translate to hiPSC-CM pharmacology.