New gene modulation methods, e.g., interference or activation CRISPR (CRISPRi/a), are deployable in a highly parallel format and allow selective perturbation of genes of interest in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). When combined with high-throughput (HT) methods for quantitative assessment of cellular responses, they provide new means for functional genomics in human heart cells and engineered tissues for translational studies. Here we demonstrate how all-optical electrophysiology, in part fueled by optogenetics for actuation and/or sensing of functional responses, can be used in conjunction with CRISPRi modulation to yield a HT platform. Our recent studies explore the possibility to use CRISPRi in post-differentiated hiPSC-CMs to selectively perturb key genes underlying cardiac electrophysiology. We validated the use of our all-optical technology for HT analysis as part of a comprehensive characterization pipeline to link electromechanical functional outputs to molecular correlates, identified by CRISPRi perturbation in hiPSC-CMs. The approach entails the short-term genetic engineering of already differentiated cells and the validation of a pipeline for mRNA or protein analysis post-functional assessment, along with correlative and dimension-reduction studies. Our results demonstrate proof of principle utility of optical methods as partner technology to CRISPRi perturbations that yield mild but specific functional changes relevant to cardiac electromechanics and remodeling during disease. This technology can be useful for multiparametric assessment of cardiotoxicity and drug testing in human cells.