The two sections of this chapter provide complementary expositions of our complex, and as yet incomplete, understanding of the biology of depression. In the first section, Adrian Dunn offers a brief historical overview of antidepressant treatments to introduce the need for conducting more extensive animal-based pharmacological validation studies of new antidepressant drugs. He describes with vivid clarity the most important behavioral tests available today to measure depressive-like symptoms in animals, such as the forced-swim test, tail-suspension test, and sucrose preference test. In addition, he discusses important biological processes that are potential markers or inducers of depression, such as the enhanced metabolism of brain tryptophan and serotonin, the inhibition of nerve regeneration in the hippocampus, and the sickness behavior induced by tumor burden and inflammatory cytokines. In the second section, Robert Dantzer and Keith Kelley offer a detailed account of the possible neuroimmune mechanisms of sickness and depression that are induced by inflammatory cytokines. They begin by describing some of the cellular changes in the brain that follow infection and inflammation in the periphery, with particular emphasis on the role of interleukin (IL)-1 and lipopolysaccharide (LPS) in the induction of neuroimmune pathways of communication. Motivational changes triggered by sensory pathways and their involvement in sickness and depression are discussed, along with the difficult task of discriminating between the two phenotypes. A detailed description is given of the possible role of indoleamine 2,3 dioxygenase (IDO) and tryptophan metabolism as one of the key molecular mechanisms that may link inflammation with depression.