Macrophages play a critical role during the immune response. Like other cells of the immune system, macrophages are produced in large amounts and most of them die through apoptosis. Macrophages survive in the presence of soluble factors, such as IFN-gamma, or extracellular matrix proteins like decorin. The mechanism toward survival requires the blocking of proliferation at the G1/S boundary of the cell cycle that is mediated by the cyclin-dependent kinase (cdk) inhibitor, p27kip and the induction of a cdk inhibitor, p21waf1. At the inflammatory loci, macrophages need to proliferate or become activated in order to perform their specialized activities. Although the stimuli inducing proliferation and activation follow different intracellular pathways, both require the activation of extracellular signal-regulated kinases (ERKs) 1 and 2. However, the kinetics of ERK-1/2 activation is different and is determined by the induction of the MAP-kinase phosphatase-1 (MKP-1) that dephosphorilates ERK-1/2. This phosphatase plays a critical role in the process of proliferation versus activation of the macrophages.