Recent years have seen the design and implementation of many optical activatable smart probes. These probes are activatable because they change their optical properties and are smart because they can identify specific targets. This broad class of detection agents has allowed previously unperformed visualizations, facilitating the study of diverse biomolecules including enzymes, nucleic acids, ions and reactive oxygen species. Designed to be robust in an in vivo environment, these probes have been used in tissue culture cells and in live small animals. An emerging class of smart probes has been designed to harness the potency of singlet oxygen generating photosensitizers. Combining the discrimination of activatable agents with the toxicity of photosensitizers represents a new and powerful approach to disease treatment. This review highlights some applications of activatable smart probes with a focus on developments of the past decade.