The success of clinical treatments is highly dependent on early detection and much research has been conducted to develop fast, efficient, and precise methods for this reason. Conventional methods relying on nonspecific and targeting probes are being outpaced by so‐called nanosensors. Over the last two decades a variety of activatable sensors have been engineered, with a great diversity concerning the operating principle. Therefore, this review delineates the achievements made in the development of nanosensors designed for diagnosis of diseases. Activatable nanosensors are a promising technology platform for detecting and grading diseases efficiently even at early stage of disease. This literature review aims to delineate the progression of nanosensor designs regarding their principles of activation and application. Nanosensors can be activated via target interaction with enzyme, RNA, DNA, protein, or via physiological changes induced by pH, reactive oxygen species/nitrogen species, or glutathione interaction.