Small iontophoretic application of wheat-germ-agglutinin conjugated to horseradish peroxidase, was used to simultaneously observe, in the rat, the afferent and the efferent connections of the cuneiformis nucleus (Cnf), in the same animal. The results demonstrate that the main Cnf afferent connections originate from: (1) 6 regions of the forebrain: the nucleus centralis of the amygdala, the zona incerta, the dorsomedial, ventromedial and the lateral area of the hypothalamus and the periventricular gray matter and (2) 4 regions of the midbrain: the substantia nigra pars lateralis, the peripeduncular area, the periaqueductal gray matter and the other side Cnf. In contrast to the wealth of origins of afferent fibers, most projections of the Cnf are concentrated to the B3 area and the bordering reticular nuclei. It is proposed that the Cnf, which mostly receives afferent connections from the forebrain and the midbrain, and which in turn densely projects on the B3 area, is a relay for the modulation of pain processes.