The acute inflammatory response occurs as a result of tissue injury or infection and is characterized by the coordinated recruitment of leukocytes in response to inflammatory mediators including chemokines. This process generally resolves within a matter of days, and normal tissue architecture is restored by a process of wound healing. Failure to resolve the injury can result in chronic inflammation. Much of our understanding of the specific mediators and cell types involved in acute inflammation has come from sterile peritonitis models. The injection of a wide range of irritants into the peritoneal cavity induces the hallmarks of inflammation, including pain, leukocyte infiltration, and synthesis of inflammatory mediators. Intraperitoneal injection of zymosan, a polysaccharide cell wall component derived from Saccharomyces cerevisiae, has been widely used as a self-resolving model of acute inflammation that peaks within a few hours and is cleared within 48 to 72 h. We have used the zymosan-induced peritonitis model extensively to quantify the recruitment of monocytes and neutrophils into the peritoneal cavity and to study the effects of existing and novel antiinflammatory drugs. We discuss some of the applications and advantages of the zymosan-induced peritonitis model and describe the method for analysis of leukocyte recruitment and inflammatory mediator production in response to zymosan.