New approach methodologies (NAMs) offer improved chemical safety assessment by providing more protective and relevant models with reduced reliance on animals. Despite their benefits, barriers such as scientific, technical, legislative, economic, and cultural issues hinder their adoption. This article explores these barriers and how they can be overcome to promote the wider use of NAMs in chemical safety science, exposure, hazard, and risk assessment. It outlines short-, mid-, and long-term goals to enhance human and environmental protection through a new paradigm incorporating exposure science and a culture promoting protective toxicological risk assessments. NAMs include in vitro, in chemico, and in silico methods that enable improved chemical safety assessment. They are not intended to replace animal tests but to provide more relevant information for exposure-based safety assessments. NAMs have been successfully used for specific toxicity endpoints, such as skin irritation and sensitization, and have shown comparable or superior performance to traditional animal tests. However, challenges remain in translating NAMs into practical use, particularly within regulatory contexts. NAMs may not fully replicate animal test results but can provide more relevant data for human hazard and risk assessment. They are a human-focused approach that can be conceptually different from traditional whole-animal testing. NAMs can be benchmarked against animal data, but their acceptance is influenced by regulatory expectations and the reliability of data. There is a need for confidence in NAMs to ensure their use in regulatory decision-making. Regulatory acceptance of NAMs is growing, but there are inconsistencies and ambiguities across geographies and sectors. The success of NAMs depends on a shift in mindset, with a focus on risk-based approaches and the integration of exposure science. There is a need for policy changes, regulatory reform, and infrastructure development to support the adoption of NAMs. The use of NAMs in regulatory decision-making is supported by the development of new tools and approaches, including computational models, high-throughput assays, and machine learning. These tools can help address complex endpoints and improve the accuracy of safety assessments. However, there are still challenges in validating NAMs and ensuring their acceptance by regulatory authorities. Economic barriers also hinder the adoption of NAMs, with concerns about the cost and uncertainty of investment. There is a need for a viable economic transition plan to ensure the financial sustainability of CROs and industry. The successful adoption of NAMs will require a shift in thinking, with a focus on risk-based approaches and the integration of NAMs into regulatory frameworks. The future of NAMs depends on continued research, investment, and collaboration between industry, academia, and regulators. There is a need for a new paradigm in toxicological risk assessment that incorporates NAMs and promotes the use of protective toxicological risk assessments. This will require significant investment in training, education, and the development of new tools and approaches to ensure the full benefits of NAMs are realized.New approach methodologies (NAMs) offer improved chemical safety assessment by providing more protective and relevant models with reduced reliance on animals. Despite their benefits, barriers such as scientific, technical, legislative, economic, and cultural issues hinder their adoption. This article explores these barriers and how they can be overcome to promote the wider use of NAMs in chemical safety science, exposure, hazard, and risk assessment. It outlines short-, mid-, and long-term goals to enhance human and environmental protection through a new paradigm incorporating exposure science and a culture promoting protective toxicological risk assessments. NAMs include in vitro, in chemico, and in silico methods that enable improved chemical safety assessment. They are not intended to replace animal tests but to provide more relevant information for exposure-based safety assessments. NAMs have been successfully used for specific toxicity endpoints, such as skin irritation and sensitization, and have shown comparable or superior performance to traditional animal tests. However, challenges remain in translating NAMs into practical use, particularly within regulatory contexts. NAMs may not fully replicate animal test results but can provide more relevant data for human hazard and risk assessment. They are a human-focused approach that can be conceptually different from traditional whole-animal testing. NAMs can be benchmarked against animal data, but their acceptance is influenced by regulatory expectations and the reliability of data. There is a need for confidence in NAMs to ensure their use in regulatory decision-making. Regulatory acceptance of NAMs is growing, but there are inconsistencies and ambiguities across geographies and sectors. The success of NAMs depends on a shift in mindset, with a focus on risk-based approaches and the integration of exposure science. There is a need for policy changes, regulatory reform, and infrastructure development to support the adoption of NAMs. The use of NAMs in regulatory decision-making is supported by the development of new tools and approaches, including computational models, high-throughput assays, and machine learning. These tools can help address complex endpoints and improve the accuracy of safety assessments. However, there are still challenges in validating NAMs and ensuring their acceptance by regulatory authorities. Economic barriers also hinder the adoption of NAMs, with concerns about the cost and uncertainty of investment. There is a need for a viable economic transition plan to ensure the financial sustainability of CROs and industry. The successful adoption of NAMs will require a shift in thinking, with a focus on risk-based approaches and the integration of NAMs into regulatory frameworks. The future of NAMs depends on continued research, investment, and collaboration between industry, academia, and regulators. There is a need for a new paradigm in toxicological risk assessment that incorporates NAMs and promotes the use of protective toxicological risk assessments. This will require significant investment in training, education, and the development of new tools and approaches to ensure the full benefits of NAMs are realized.