Animal models have shaped biomedical testing for decades, but scientific limitations, economic pressure, and ethical concerns are driving a transition toward New Approach Methodologies (NAMs). These human cell-based models offer a more relevant framework for improving translational insight. However, their value depends on assay design and an understanding of the biological question. Human variability should be incorporated into experimental design rather than minimized. The future impact of NAMs depends on developing assays that are biologically relevant, robust, and informative for decision-making.