Monoamines are well known to modulate locomotion in several vertebrate species. Co-application of DA and 5-HT has also been shown to potently induce fictive locomotor rhythms in isolated spinal cord preparations. However, a synergistic contribution of these monoamines to locomotor rhythmogenesis in vivo has never been examined. Here, we characterized the effects induced by selective DA and 5-HT receptor agonists on hindlimb movement induction in completely spinal cord-transected (adult) mice. Administration of the lowest effective doses of SKF-81297 (D_1/5 agonist, 1-2 mg/kg, i.p.) or 8-OH-DPAT (5-HT_1A/7 agonist, 0.5 mg/kg, i.p.) acutely elicited some locomotor-like movements (5.85 ± 1.22 and 3.67 ± 1.44 LM per min, respectively). Co-administration of the same doses of SKF-81297 and 8-OH-DPAT led to a significant increase (seven- to ten-fold) of LM (37.70 ± 5.01 LM/min). Weight-bearing and plantar foot placement capabilities were also found with the combination treatment only (i.e., with no assistance or other forms of stimulation). These results clearly show that D_1/5 and 5-HT_1A/7 receptor agonists can synergistically activate spinal locomotor networks and, hence, generate powerful basic stepping movements in complete paraplegic animals. While previous work from this laboratory has reported the partial rhythmogenic potential of monoamines in vivo, the present study shows that drug combinations such as SKF-81297 and 8-OH-DPAT can elicit weight-bearing stepping.