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The development of chemically compatible microsystems that can operate across expanded process conditions, such as high pressures (HP) and high temperatures (HT), is of great interest for many applications, including high pressure chemistry and hydrothermal and supercritical fluid processes. We present a methodology for the successful design and use of HP/HT microsystems. Key parameters for the fabrication of microreactors and modular fluidic packaging able to withstand severe pressure and temperature conditions (30 MPa, 400 °C) are described. Applications of these HP/HT plug and play microsystems are illustrated with examples, including multiphase flow visualization through the transition of liquid−liquid immiscible hexane−water segmented flow to homogeneous supercritical flow, on chip supercritical water oxidation, and synthesis of iron oxide nanoparticles.