The MEHTRICS proposal aims to challenge the current limits of HT cell-based screening by combining HT-RNAi with an emerging new technology for normalizing cultured cell behaviors, namely the growth of cells on adhesive micropatterns. Initial applications of this technology have already demonstrated its potential for enhancing the quality of existing high content analyses by radically reducing the cell population’s phenotypic variability, resulting in much lower cell sampling requirements. This approach also promises to open up major new “assay development space” by broadening the range of analysis strategies that drive the novel cell-based assay designs, whose evolution has otherwise stagnated in recent years. The consortium will carry out several parallel and complementary lines of development to diversify the applicability of the MEHTRICS platform for both academic and industrial uses, ultimately validating the new capabilities through proof of principle screens. Our key objectives are 1) to optimize micropattern geometries and compositions to accommodate extended timelines typical of siRNA assays, 2) to integrate the promising Transfected Cell Array (TCA) technique to decrease cost and increase throughput, 3) to develop novel cell models of key diseases based on micropatterned adult stem cells and polarized epithelia/endothelial architectures and 4) to validate each of these implementations in key industry-relevant siRNA screening applications. Since experimental designs required to run RNAi screens are among the most demanding of all HT/HC studies and encompass virtually all technical challenges also encountered in compound screens, we expect the proposed scope of activities to deliver the maximal potential for impactful innovation, widespread adoption and clear relevance for all major applications of HT/HC cell screening. The resulting new tools and methodologies will be incorporated into the commercial offerings of the consortium’s two key SMEs, CYTOO and CENIX.