Metabolic syndrome as a clustering of risk factors for diabetes and cardiovascular disease affects both men and women, but with important gender differences. Animal models have been used to understand disease progression and define therapeutic options, but most pre-clinical research on metabolic syndrome is undertaken in males. This opinion piece discusses the differences in male and female physiology that may influence both the development and the responses to pharmacological interventions of metabolic disorders, especially obesity. An appreciation of gender differences should improve the design and usefulness of biomedical experimental research to allow the development of relevant gender-based treatment options for chronic diseases including obesity, metabolic and cardiovascular diseases.