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As metabolic diseases continue to rise globally, preclinical models remain essential for uncovering disease mechanisms and evaluating potential therapies. While diet is a key driver of metabolic phenotypes, it is often an underappreciated variable in study design and interpretation. This seminar will examine the differences between grain-based chow and purified ingredient diets, and explain why purified diets are widely used to induce disease models in a controlled and reproducible manner. The talk will explore how specific dietary components are used to drive phenotypes relevant to obesity, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease (MASLD), and will highlight the importance of matched control diets in minimizing confounding variables and enhancing translational relevance.