Diet and nutrition are intricately related to cancer prevention, growth, and treatment response. Preclinical rodent models are a cornerstone to biomedical research and remain instrumental in our understanding of the relationship between cancer and diet and in the development of effective therapeutics. However, the success rate of translating promising findings from the bench to the bedside is suboptimal. Well-designed rodent models will be crucial to improving the impact basic science has on clinical treatment options. This review discusses essential experimental factors to consider when designing a preclinical cancer model with an emphasis on incorporatingthese models into studies interrogating diet, nutrition, and metabolism. The aims of this review are to ( a ) provide insight into relevant considerations when designing cancer models for obesity, nutrition, and metabolism research; ( b ) identify common pitfalls when selecting a rodent model; and ( c ) discuss strengths and limitations of available preclinical models.