Much evidence suggests a cross-talking between nerve fibers and the immunity system. The immunomodulation by substance P includes cell activation and proliferation of human cells, with cytokine and chemokine generation and release. Substance P was first isolated by Leeman et al. as an undecapeptide with important neurotransmitter-neuromodulator effects. In addition, substance P was shown to induce and mediate inflammation, angiogenesis, infections, intestinal mucosal immunity and stress. Substance P is able to activate several immune cells, such as CD4+ and CD8+ T lymphocytes, mast cells, NK cells and macrophages. In recent studies we have shown that substance P can activate interleukin-8, a CXC chemokine, demonstrating its involvement in immune cell chemoattraction. We believe that substance P is important in understanding the pathophysiology of inflammation.