Reactive oxygen, nitrogen and sulfur species (RONSS) collectively encompasses a variety of energetically dynamic entities that emerge as inherent characteristics of aerobic life. This broad category includes reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS). A conundrum arises from the indispensable role of RONSS in redox signalling, while its overproduction in the mitochondria poses deleterious effects. This imbalance leads to biomolecular damage and contributes to neurodegenerative disorders, cancer, cardiovascular diseases and inflammation. Notably, the differential roles of RONSS across various diseases can be strategically exploited for therapeutic interventions. Timely, precise, and sensitive detection methods are indispensable for elucidating the spatiotemporal dynamics of RONSS and evaluating disease pathogenesis and progression. By monitoring RONSS levels, we can discern early markers of disease onset, enabling proactive intervention strategies for effective disease management. Therapeutic interventions targeting oxidative/nitrosative stress in disease pathologies have proven to be effective treatment routes in the mitigation of different diseases. This review aims to offer a comprehensive overview of the functional implications and delicate balance of RONSS in disease conditions, and advances made in detection strategies over the years while offering therapeutic strategies to tackle their adverse effects. A special emphasis is focussed on neurodegenerative disorders and cancer with case studies using RONSS-targeted chemical probes and prodrugs.