This article is part of a Special Issue Energy Balance.
Over the past two decades, and in particular over the past 5–7 years, there has been a tremendous advancement in the understanding of the metabolic control of reproductive physiology. This has been in large part due to the advancement and refinement of gene targeting tools and techniques for molecular mapping. Yet despite the emergence of exciting and often times thought-provoking data through the use of new mouse models, the heavy reliance on gene targeting strategies has become fundamental in this process and thus caution must be exercised when interpreting results. This minireview article will explore the generation of new mouse models using genetic manipulation, such as viral vector delivery and the use of the Cre/loxP system, to investigate the role of circulating metabolic hormones in the coordination of reproductive physiology. In addition, we will also highlight some of the pitfalls in the use of genetic manipulation in the current paradigms. However, it has become clear that metabolic cues employ integrated and plastic neural circuits in order to modulate the neuroendocrine reproductive axis, and despite recent advances much remains to be elucidated about this circuitry.