This paper summarizes the results of some of our previous neuroanatomical and immunohistochemical studies on the organization of the striatum and its efferent projections in rodents, monkeys and humans. It also reports recent functional calcium-imaging data obtained in rat brain slices, as well as developmental results gathered with bromodeoxyuridine (BrdU) in monkeys. On one hand, single-axon tracing studies in rats and monkeys have revealed that the majority of striatofugal axon arborizes within most striatal target structures. In humans, SP-positive fibers were found to arborize in the two segments of the globus pallidus, where they were closely apposed to pallidal neurons that expressed the neurokinin-1 receptor (NK-1r). In agreement with such findings, calcium-imaging studies in rats have revealed that pallidal and nigral neurons are both responsive to SP. These findings suggest that the striatofugal projection system is much more widely distributed than previously thought and exerted a multifaceted effect upon its target sites. On the other hand, immunostaining studies in humans have shown the presence of several types of putative dopaminergic neurons intrinsic to the striatum. Furthermore, BrdU labeling experiments in monkeys have demonstrated that new neurons are generated throughout adult life in the striatum of normal monkeys and that their number can be markedly increased by the administration of neuronal growth factors. These findings open new therapeutic avenues for the treatment of neurodegenerative disorders that specifically affect the striatum.