Various intercellular signals influence the strength and mode of synaptic neurotransmission and contribute to synaptic plasticity. Such signals include neurotransmitters, gas molecules, and protein factors. In response to certain neural stimuli, these molecules are liberated from presynaptic and postsynaptic neurons, glial cells, and immune cells and synergistically alter synaptic neurotransmission over the long or short term. The short-term actions often involve presynaptic activities leading to long-term potentiation. However, it is now known that various protein factors including growth factors, cytokines, and neurotrophic factors can produce not only such short-term effects but also long-term synaptic modification of presynaptic and postsynaptic neurons by altering the production of neurotransmitters and the expression of their receptors or synaptic organization. The present review focuses on these intercellular protein factors and discusses the way in which they regulate synaptic plasticity.