Cold atmospheric plasma (CAP) medicine is an emerging field that applies plasma science to biomedical applications. CAP, generated at low temperatures, has been used in dermatology, oncology, and antimicrobial strategies. Despite clinical use, the exact mechanisms of CAP treatment on cells remain unclear. CAP can influence immune cells, offering potential for immunomodulation, anti-infective therapies, and inflammation regulation. This review discusses the history, current state, and future directions of plasma medicine, focusing on CAP applications, challenges, and opportunities for predictive control. CAP is generated via dielectric barrier discharges (DBDs) and atmospheric pressure plasma jets (APPJs), with various configurations affecting treatment outcomes. CAP treatments have shown promise in wound healing, sterilization, and cancer therapy. However, defining a unit dose for plasma therapeutics remains a challenge due to the variability of CAP, its target-specific responses, and the complexity of its physico-chemical and biological effects. The main effectors of CAP treatment are reactive oxygen and nitrogen species (RONS), which interact with tissues to induce biological activity. CAP treatments can also affect immune cells, such as neutrophils and macrophages, through mechanisms involving ROS, NET formation, and cytokine release. In oncology, CAP has shown potential in inhibiting cancer cell growth, with studies indicating its ability to induce apoptosis and increase DAMP production. However, the tumor microenvironment may interfere with CAP treatments. The effects of CAP on intracellular targets, such as aquaporins and signaling pathways like Nrf2 and Notch, are also being investigated. Overall, CAP holds promise for various biomedical applications, but further research is needed to define its therapeutic potential and optimize its use in clinical settings.Cold atmospheric plasma (CAP) medicine is an emerging field that applies plasma science to biomedical applications. CAP, generated at low temperatures, has been used in dermatology, oncology, and antimicrobial strategies. Despite clinical use, the exact mechanisms of CAP treatment on cells remain unclear. CAP can influence immune cells, offering potential for immunomodulation, anti-infective therapies, and inflammation regulation. This review discusses the history, current state, and future directions of plasma medicine, focusing on CAP applications, challenges, and opportunities for predictive control. CAP is generated via dielectric barrier discharges (DBDs) and atmospheric pressure plasma jets (APPJs), with various configurations affecting treatment outcomes. CAP treatments have shown promise in wound healing, sterilization, and cancer therapy. However, defining a unit dose for plasma therapeutics remains a challenge due to the variability of CAP, its target-specific responses, and the complexity of its physico-chemical and biological effects. The main effectors of CAP treatment are reactive oxygen and nitrogen species (RONS), which interact with tissues to induce biological activity. CAP treatments can also affect immune cells, such as neutrophils and macrophages, through mechanisms involving ROS, NET formation, and cytokine release. In oncology, CAP has shown potential in inhibiting cancer cell growth, with studies indicating its ability to induce apoptosis and increase DAMP production. However, the tumor microenvironment may interfere with CAP treatments. The effects of CAP on intracellular targets, such as aquaporins and signaling pathways like Nrf2 and Notch, are also being investigated. Overall, CAP holds promise for various biomedical applications, but further research is needed to define its therapeutic potential and optimize its use in clinical settings.