Neuromodulators, including dopamine (DA), serotonin (5HT), and acetylcholine (ACh), are intrinsic components of higher cognitive functioning and contribute to key processes involved in human intellect and language capabilities. Additionally, each neuromodulator system is involved in uniquely human neuropathologies that demonstrate cognitive deficits such as schizophrenia, Alzheimer’s and Parkinson’s diseases. The roles of DA, 5HT, and ACh in cognition make them excellent candidate neural substrates for modification in the evolution of human cognitive specializations. It has largely been assumed that that humans have denser cortical innervation by one or more of the neuromodulators, responsible for the unique mental acumen that humans display. The present research was designed to assess the possibility that the evolution of human intellectual capacities were supported by changes in the anatomical supply of neuromodulators to the frontal cortex. To this end, quantitative comparative analyses were performed for each neuromodulator among humans, chimpanzees, and macaques. Immunohistochemical methods were used to visualize neuromodulator axons within the cerebral cortex. Prefrontal cortical areas 9 and 32 were chosen for evaluation due to their roles in working memory and theory of mind, respectively. Primary motor cortex (area 4) was also evaluated because it is not associated with higher cognitive functions. The findings revealed that humans do not display a quantitative increase in frontal cortical neuromodulator innervation. However, the results indicate that there was a region- and lamina-specific increase in DA, 5HT, and ACh innervation that occurred after hominoid and Old World monkeys split during the Miocene. This change was detected in cortical areas 9 and 32, but not in primary motor cortex. Humans and chimpanzees exhibited an increased neuromodulator to neuron density in layers III and V/VI for both DA and ACh, and an increase in layers V/VI for 5HT. Further, several morphological specializations were observed in humans and chimpanzees that were absent in macaques. These features may represent a greater capacity for cortical plasticity exclusive to hominoids (i.e., humans and chimpanzees). Taken together, these results indicate a significant reorganization of cortical neuromodulator transmission in humans and chimpanzees that may underlie cognitive capacities shared by all hominoids.