p21(WAF1/CIP1) (p21) is a crucial CDK inhibitor that controls the cell cycle. This molecule is also involved in the regulation of apoptosis and gene expression. However, like many other cell regulators, the functional activity of p21 depends on its cellular context and is controlled through phosphorylation and protein-protein interactions. p21 is also important in cells of the immune system regulating the cell cycle and preventing apoptosis of macrophages. In this issue of the European Journal of Immunology, two reports investigate the role of p21 further determining its critical role as a negative regulator of macrophage activation, in particular inhibiting the LPS-dependent induction of TNF-alpha and IL-1beta. The inhibition mediated by p21 is shown to be related to NF-kappaB activity. Furthermore, the observation that p21(-/-) mice are more susceptible to septic shock supports the notion that p21 is a negative regulator of macrophage activation and therefore a potential new target to control inflammatory diseases.