Inflammation is viewed as a protective response against insults to the organism. It involves the recruitment of many cell types and the production of various inflammatory mediators in attempts to contain and reverse the insult. However, inflammation can lead to irreversible tissue destruction by itself and, therefore, can represent a disease state that causes significant morbidity and mortality. Understanding the molecular mechanisms controlling the inflammatory response is essential to formulate therapeutic strategies for the treatment of inflammatory conditions. In fact, substantial research has unveiled important aspects of the inflammatory machinery, both at the cellular and molecular levels. Recently, sphingolipids (SLs) have emerged as signaling molecules that regulate many cell functions, and ample evidence emphasizes their role in the regulation of inflammatory responses. Here, we review the role of bioactive SL as regulators and mediators of inflammatory responses.