Prominent projections of the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAS) and the ventral tegmental area (VTA) exist, but it has been difficult to assign a clear functional role to either of these projections. With some exceptions to be discussed in some detail, only a few neurochemical and behavioral effects of manipulating the mPFC can be explained by invoking the mPFC-NAS projection, while most effects are compatible with an involvement of the mPFC-VTA-NAS or mPFC-pedunculopontine tegmental nucleus (PPTg)-VTA-NAS circuits. What is known about the organization and function of these loops is generally consistent with the results obtained by stimulating or lesioning or injecting drugs into the mPFC, yet these findings are largely inconsistent with the functional organization of the mPFC-NAS projection. This review briefly summarizes some of the most important aspects of what is known about the functional interactions of the mPFC. NAS, VTA, and associated areas, and focuses on functional differences between the mesocortical and the mesoaccumbal dopaminergic projections, and between the corticomesencephalic and the corticoaccumbal glutamatergic projections.