BACKGROUND: Synaptic plasticity, the basic mechanism of clinical recovery after brain lesion, can also remarkably influence the clinical course of multiple sclerosis (MS). Physical rehabilitation represents the main treatment option to promote synaptic long-term potentiation (LTP) and to enhance spontaneous recovery of neurological deficits. OBJECTIVES: To overview the role of pharmacological treatment and physical rehabilitation in modulating LTP and enhancing clinical recovery in MS. RESULTS: Drug-induced LTP enhancement can be effectively used to promote functional recovery, alone or combined with rehabilitation. Also, as inflammatory cytokines alter synaptic transmission and plasticity in MS, pharmacological resolution of inflammation can positively influence clinical recovery. Finally, physical exercise could be an independent factor able to preserve or enhance LTP reserve both influencing signaling pathways involved in plasticity induction and maintenance, and decreasing inflammation. FUTURE DIRECTIONS: Better knowledge of LTP determinants may be useful to design specific strategies to promote recovery after a relapse and to reduce the progressive neurological deterioration in MS patients.