Caspases are a family of proteases that play critical roles in controlling inflammation and cell death. Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells, whereas anomalistic cell apoptosis may be associated with many diseases. The detection and imaging of caspase-3 will be of great significance in evaluating the early therapeutic effect of tumors. Developing smart fluorescent probes may be helpful for the visualization of therapeutic effect compared with “always on” probes. Thus, more and more works toward activatable fluorescent probes for caspase-3 imaging have been reported. In addition, multifunctional probes have also been designed to further improve the imaging of caspase-3. Herein, this review systematically summarized the representative work of caspase-3 from the perspective of molecular design that it will play a guiding role in the design of probes that respond to caspase-3. Also, challenges and perspectives toward the field for imaging of cell apoptosis (caspase-3) are also discussed.