The hypothalamus is responsible for the control of many of our physiological responses, including energy homeostasis. Of interest, there are a number of instances of sexual dimorphism documented with regard to metabolic processes. This review will discuss the necessity of utilizing both male and female models when studying the mechanisms underlying energy homeostasis, particularly those originating at the level of the hypothalamus. Because obesity often results in central neuroinflammation, we describe markers that could be used to study differences between male and female models, both the whole organism and also at the cellular level. Our laboratory has generated a wide array of immortalized hypothalamic cell models, originating from male and female rodents that we suggest could be beneficial for these types of studies. It is imperative that both sexes are considered before any recommendations for therapeutic interventions are considered.