Throughout life, neuronal network properties are modulated according to both external and internal stimuli. These adaptive capabilities of the central nervous system (CNS) have been generically termed "plasticity". One prominent form of CNS plasticity is the capability of synapses to change their strength. Synaptic strength is not a constant value but depends at each moment on the synapse's past activity. These changes in transmission efficacy are called activity-dependent synaptic plasticity (ADSP) and result in an increase (potentiation) or a decrease (depression) in synaptic strength. The ability of synapses to express one type of ADSP can change as a function of previous plasticity and previous activation of synapses. This plasticity of synaptic plasticity has been termed metaplasticity. ADSP and metaplasticity are now regarded as essential mechanisms for normal information processing in neuronal networks. Rhythmic activities such as locomotion are generated by rhythmically active central neuronal networks called central pattern generators (CPGs) that possess the intrinsic ability to generate rhythmic and organized activity in the absence of sensory inputs. The CPG activity arises from a complex dynamic interaction between synaptic transmission, intrinsic membrane properties and neuromodulatory inputs. A growing body of evidence suggests that the spinal cord matches the plastic and metaplastic properties found in other parts of the CNS, both under normal conditions and after spinal cord injury. Here, findings describing ADSP and its neuromodulation in vertebrate sensorimotor networks are reviewed, followed by a discussion of the potential role of ADSP and neuromodulation in the physiology and pathophysiology of motor circuit assembly.