Chemical sensors for detection of biological analytes in their native settings with spatial and temporal resolution can enable the study of their physiological and pathological contributions by molecular imaging. An emerging area of sensor research is activity-based sensing (ABS), which leverages the unique chemical reactivity of a given analyte of interest, rather than traditional binding-based approaches that rely on lock-and-key molecular recognition, to achieve selectivity in the complex biological environments. This chapter summarizes foundational design principles of ABS and provides a survey of three representative examples of activity-based imaging probes using oxidative, reductive, or redox-neutral reactivity for selective analyte detection, highlighting the broad applicability of this synthetic reaction chemistry approach to identify and characterize new biology.