Botulinum toxin (BT) acts peripherally by inhibiting acetylcholine release from the presynaptic neuromuscular terminals and by weakening muscle contraction. Therefore, its clinical benefit is primarily due to its peripheral action. As a result, local injection of BT has become a successful and safe tool in the treatment of several neurological and non-neurological disorders. Studies in animals have also shown that the toxin can be retrogradely transported and even transcytosed to neurons in the central nervous system (CNS). Further human studies have suggested that BT could alter the functional organisation of the CNS indirectly through peripheral mechanisms. BT can interfere with and modify spinal, brainstem and cortical circuits, including cortical excitability and plasticity/organisation by altering spindle afferent inflow directed to spinal motoneurons or to the various cortical areas. It is well demonstrated that the distant CNS effects of BT treatment parallel the peripheral effect, although there is limited evidence as to the cause of this. Therefore, further studies focussed on central changes after BT treatment is needed for a better understanding of these non-peripheral effects of BT.