Major depressive disorder (MDD) is a central nervous system disorder characterized by the culmination of profound disturbances in mood and affective regulation. Animal models serve as a powerful tool for investigating the neurobiological mechanisms underlying this disorder; however, little standardization exists across the wide range of available modeling approaches most often employed. This review will illustrate some of the most challenging obstacles faced by investigators attempting to associate depressive-like behaviors in rodents with symptoms expressed in MDD. Furthermore, a novel series of depressive-like criteria based on correlating behavioral endophenotypes, novel in vivo neurophysiological measurements, and molecular/cellular analyses within multiple brain are proposed as a potential solution to overcoming this barrier. Ultimately, linking the neurophysiological and cellular/biochemical actions that contribute to the expression of a defined MDD-like syndrome will dramatically extend the translational value of the most valid animal models of MDD.