Cell and gene therapies, including CAR T-cells, CRISPR-based genome editing, and next-generation viral and non-viral delivery platforms, are transforming treatment paradigms across cancer, rare genetic disorders, immune dysregulation, and neurodegenerative disease. These therapies offer curative potential but also present safety challenges owing to prolonged biological activity, systemic immune engagement, and lasting genomic alterations. This review examines the range of related toxicities, including immune complications, genotoxicity, and organ-specific effects, with attention to atypical presentations, gaps in clinical trial safety capture, and disparities in global long-term follow-up infrastructure. Central to our analysis is a risk-adaptive, digitally enabled pharmacovigilance model that incorporates real-world data, artificial intelligence-based signal detection, and seamless pediatric-to-adult follow-up to proactively protect patients while supporting innovation. Integrated safety dashboards, pediatric transition roadmaps, and predictive monitoring tools are proposed as practical solutions to improve coordination among sponsors, regulators, and clinical sites. We also outline best practices for aligning risk evaluation and mitigation strategies with risk management plans and examine how wearable biosensors, electronic patient-reported outcomes, and multi-omics biomarkers contribute to near real-time safety surveillance. Ethical priorities such as informed consent, data privacy, and equitable access are addressed throughout. By positioning pharmacovigilance as a proactive and predictive foundation within the therapeutic landscape, this review offers a forward-looking blueprint to advance innovation while ensuring long-term patient safety.