Amyotrophic lateral sclerosis is a neurodegenerative disorder that results in the selective death of motor neurons in the central nervous system. This progressive motor neuron degeneration leads to death of the patient on average three to five years after onset of the disease. To date, no therapy is available. Many hypotheses have been formulated to explain the selective degeneration of motor neurons. One of the most studied hypotheses is the putative role of the inflammatory response that accompanies motor neuron death. The proliferation of microglia and astrocytes has been considered to be a secondary phenomenon, but recently, evidence is accumulating in favour of a contributory role of the non-neuronal cell populations to the pathogenesis of the disease. In this review, we will introduce the characteristics of microglial cells in the central nervous system. We will summarize the evidence of the expansion and the activation of the microglial cell population that accompanies motor neuron degeneration. Finally, an overview will be given of the different therapeutic strategies that targeted the inflammatory process in amyotrophic lateral sclerosis.