Abstract Photoacoustic imaging (PAI) uniquely merges the molecular contrast of optical absorption with the centimeter‐scale penetration afforded by ultrasound detection, enabling noninvasive visualization of deep physiology beyond the reach of purely optical modalities. Conventional photoacoustic (PA) contrast agents have been used to improve detection sensitivity relative to endogenous absorbers, but their fixed optical properties limit adaptation to heterogeneous or evolving disease microenvironments. Activatable PAI contrast agents overcome this drawback by switching their absorbance spectra in real time in response to exogenous triggers (near‐infrared light, heat, ultrasound, and electromagnetic fields) or endogenous microenvironmental cues (hypoxia, pH, reactive oxygen species, glutathione, and disease‐related enzymes). These dynamic features extend PAI beyond static signal enhancement, enabling user‐controlled activation, suppression of background interference, and access to functional or molecular biomarkers that conventional agents cannot provide. This review surveys recent advances in the molecular design, activation chemistry, and biomedical applications of these “activatable” probes, highlighting strategies for noninvasive diagnosis, multimodal imaging, remote actuation, and synergistic theranostics. Looking ahead, the next frontier lies in pathology‐tailored probes that can noninvasively reveal biomarkers inaccessible to current methods, as illustrated by early successes in atherosclerosis imaging. Achieving this translation will require optimizing probe safety and clearance, standardizing characterization protocols, and integrating hybrid imaging platforms with quantitative PA tomography to generate reliable diagnostic metrics.