Photoacoustic (PA) imaging, as a new type of imaging technique that offers strong optical absorption contrast and high ultrasonic resolution, shows great application prospects in the early disease diagnosis for its characteristics of deep tissue penetration and high spatial resolution. However, traditional "always on" PA contrast agents have many disadvantages such as low signal-to-noise ratio, poor selectivity and specificity. In contrast, activatable PA contrast agents, where the imaging signal can be changed in response to pathologic parameters, have shown decreased background signal and improved selectivity and specificity in early disease detection. Moreover, these contrast agents can obtain pathological parameters and information of various diseases at the molecular level by rational design to their structures, providing important guidelines for the optimization of treatment options. Therefore, activatable PA contrast agents hold greater promise in clinical practice than traditional "always on" PA contrast agents. In this review, we describe the recent advances in the development of activatable PA contrast agents. The design mechanisms and proof-of-concept applications of these activatable PA contrast agents are summarized in detail. The use of these activatable probes to detect different pathologic parameters (such as metal ions, enzymes, reactive nitrogen and reactive oxygen) is highlighted. Finally, current challenges and future perspectives in this emerging field are also analyzed.