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Mammalian cells collectively maintain a consistent internal milieu that supports their host’s survival in varying and uncertain environments. This homeostasis is often achieved through negative feedback loops that act at various levels of biological organization, from the system and organ levels down to gene expression at the molecular scale. Recently, a molecular regulatory motif has been discovered that enables a regulated variable to adapt perfectly (at the steady state) to network and parameter changes and to persistent environmental perturbations. The regulatory motif that achieves this robust perfect adaptation property realizes integral feedback, a control strategy that employs mathematical integration in a negative feedback loop. Here, we present the first synthetic implementation of integral feedback in mammalian cells. We show that this implementation successfully maintains constant levels of a transcription factor, even when its degradation is significantly increased. Furthermore, we establish the structural robustness properties of our controlled system by demonstrating that perturbing the network topology does not affect the transcription factor levels. We believe that the ability to robustly and predictably regulate the expression levels of genes will both become an indispensable tool for basic research as well as lead to substantial advances in the development of industrial biotechnology and cell-based therapies.