Acute inflammation, a physiologic response to protect cells from microbial infection and other noxious stimuli, is automatically terminated by endogenous anti-inflammatory and pro-resolving mediators to restore homeostatic conditions. However, if timely resolution of inflammation is failed, inflammation persists and can progress to a chronic inflammation which has long been thought as a predisposing factor to carcinogenesis. Excessive and pathologic inflammation causes DNA damage, genomic instability, epigenetic dysregulation, and alteration of intracellular signaling, all of which are involved in neoplastic transformation. To prevent chronic inflammation and resulting inflammation-promoted cancer development, understanding the process that resolves inflammation is essential. Resolution of inflammation is an active coordinated process regulated by distinct anti-inflammatory and pro-resolving endogenous lipid mediators, such as resolvins and lipoxins. The role of pro-inflammatory signaling in carcinogenesis has become more and more evident and well characterized, but the potential role of pro-resolving mediators in cancer prevention remains still elusive. In searching for an efficacious way to prevent chronic inflammation-associated cancer, the pro-resolving signal transduction pathways and their regulators should be unraveled.