This chapter explores the development and application of molecular-based computational approaches to enhance the safety of energetic and reactive substances by predicting their physico-chemical hazards and characterizing the hazardous reactions that they can involve. Case studies demonstrate the practical application of QSPR models in predicting the hazardous properties of both energetic and reactive materials. For nitro compounds, existing literature data allowed the development of QSPR models for different properties such as heat of decompositionHeat of decomposition and sensitivities. In the case of organic peroxides and self-reactive substances, experimental campaigns through collaborative projects with industry stakeholders were conducted to fill data gaps. Theoretical chemistry complements these efforts by elucidating detailed mechanistic insights into hazardous reactionsHazardous reactions. Case studies highlight how quantum chemical methods, such as density functional theory (DFT)Density Functional Theory (DFT), unravel the intricate decomposition pathways for materials like nitro compounds, ethers prone to peroxidationPeroxidation, and the compatibility of additives and contaminants with ammonium nitrate. These studies not only confirm experimental findings. They also identify key intermediates and reaction pathways crucial for understanding and predicting hazardous behaviors. Molecular-based computational approaches stand at the forefront of advancing safety measures for energetic and reactive materials. By bridging experimental gaps and providing deeper mechanistic understanding, these methods pave the way for safer industrial processes and products, ensuring a proactive approach to managing chemical hazards in diverse applications.