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© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Developing ultrasensitive chemical sensors with small scale and fast response through simple design and low-cost fabrication is highly desired but still challenging. Herein, a simple and universal sensing platform based on a hydrogel interferometer with femtomol-level sensitivity in detecting (bio)chemical molecules is demonstrated. A unique local concentrating effect (up to 109folds) in the hydrogel induced by the strong analyte binding and large amount of ligands, combined with the signal amplification effect by optical interference, endows this platform with an ultrahigh sensitivity, specifically 10−14m for copper ions and 1.0 × 10−11mg mL−1for glycoprotein with 2–4 order-of-magnitude enhancement. The specific chemical reactions between selected ligands and target analytes provide high selectivity in detecting complex fluids. This universal principle with broad chemistry, simple physics, and modular design allows for high performance in detecting wide customer choices of analytes, including metal ions and proteins. The scale of the sensor can be down to micrometer size. The nature of the soft gel makes this platform transparent, flexible, stretchable, and compatible with a variety of substrates, showing high sensing stability and robustness after 200 cycles of bending or stretching. The outstanding sensing performance grants this platform great promise in broad practical applications.