The mature functional architecture of the primate prefrontal cortex arises during a protracted period of postnatal development. Although catecholaminergic afferents arrive in the primate cortex quite early during fetal development, several lines of evidence suggest that substantial changes in the dopaminergic innervation of prefrontal cortex may occur during postnatal development. In this study, we used immunocytochemical techniques and antibodies against tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, to examine the precise time course from birth to adulthood of the maturational changes of tyrosine hydroxylase-labeled axons in prefrontal cortical areas 9 and 46 and primary motor cortex (area 4) of rhesus monkeys. In area 9, the densities of tyrosine hydroxylase-labeled axons and varicosities in the superficial and deep cortical layers remained relatively constant during postnatal development. In contrast, marked developmental changes in innervation density occurred in the middle cortical layers. For example, in deep layer III, the density of tyrosine hydroxylase-positive varicosities was relatively low and uniform in animals under 1 month of age but then increased by a factor of three in animals 2-3 months of age. The density of labeled varicosities continued to increase, reaching a peak (sixfold greater than in the youngest animals) in animals 2-3 years of age before declining to stable adult levels. Similar laminar-specific patterns of change also occurred in areas 46 and 4, although regional differences were present in the magnitude and precise time course of these developmental changes. These findings demonstrate that the innervation of monkey frontal cortex by tyrosine hydroxylase-immunoreactive axons undergoes a protracted, laminar-specific pattern of change during postnatal development that continues through adolescence and into early adulthood. These developmental refinements may interact with other modifications of cortical circuitry that underlie the functional maturation of these regions.