This article presents a generic flexible framework for an End-to-end Instrument Performance Simulation System (EIPS) for satellite atmospheric remote sensing instruments. A systematic process for developing an end-to-end simulation system based on Rodgers’ atmospheric observing system design process has been visualised. The EIPS has been developed to support the quantitative evaluation of new satellite instrument concepts in terms of performance simulations, design optimisation, and trade-off analysis. Important features of this framework include: fast radiative transfer simulation capabilities (fast computation and line-by-line like simulations), applicability across the whole electromagnetic (EM) spectrum and a number of integrated retrieval diagnostics. Because of its applicability across the whole EM spectrum, the framework can be usefully applied to synergistic atmospheric retrieval studies. The framework is continually developing and evolving, and finding applications to support and evaluate emerging instrument and mission concepts. To demonstrate the framework’s flexibility in relation to advanced sensor technologies in the microwave range, a novel superconducting transition edge sensor (TES) -based multi-spectral microwave instrument has been presented as an example. As a case study, the performance of existing multi-spectral-type microwave instruments and a TES-technology-based multi-spectral microwave instrument has been simulated and compared using the developed end-to-end simulation framework.