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The transcranial photobiomodulation (t-PBM) technique is a promising approach for the treatment of a wide range of neuropsychiatric disorders, including disorders characterized by poor regulation of emotion such as major depressive disorder (MDD). We examine various approaches to deliver red and near-infrared light to the dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) in the human brain, both of which have shown strong relevance to the treatment of MDD. We apply our hardware-accelerated Monte Carlo simulations to systematically investigate the light penetration profiles using a standard adult brain atlas. To better deliver light to these regions-of-interest, we study, in particular, intranasal and transcranial illumination approaches. We find that transcranial illumination at the F3–F4 location (based on 10–20 system) provides excellent light delivery to the dlPFC, while a light source located in close proximity to the cribriform plate is well-suited for reaching the vmPFC, despite the fact that accessing the latter location may require a minimally invasive approach. Alternative noninvasive illumination strategies for reaching vmPFC are also studied and both transcranial illumination at the Fp1–FpZ–Fp2 location and intranasal illumination in the mid-nose region are shown to be valid. Different illumination wavelengths, ranging from 670 to 1064 nm, are studied and the amounts of light energy deposited to a wide range of brain regions are quantitatively compared. We find that 810 nm provided the overall highest energy delivery to the targeted regions. Although our simulations carried out on locations and wavelengths are not designed to be exhaustive, the proposed illumination strategies inform the design of t-PBM systems likely to improve brain emotion regulation, both in clinical research and practice.