Inflammatory responses play decisive roles at different stages defending the body from harmful agents. Pro-inflammatory cytokines stimulate immune cells to release reactive oxygen and nitrogen species, of which cytotoxic effect helps not only eliminate invaders but effect on the host cells to die or induce epigenetic changes and mutations. If the immune system does not work sufficiently and the healing is incomplete, the inflammation shifts from acute to chronic repeating injury and wound-healing resulting in creating an environment that may initiate cancer. The longer the inflammation last, the higher possibility of inflammatory mediators enhance neoplastic cell proliferation and tumor growth. Furthermore, chronic inflammation facilitates and sustains tumor growth by the secreted chemokines that support the development of tumor-derived blood networks known as angiogenesis. In recent couple of years, scientists hypothesized that the cancer initiation could be linked to the development of cancer stem cells from stem/progenitor cells in tissues exposed to chronic inflammation. Definition of the relationship between inflammation, stem cell, and cancer initiation will provide an insight into the critical roles of the mediators responsible for the cancer-inducing niche. Accordingly, we could target the mediators of chronic inflammation to prevent cancer initiation. In the current chapter, we will try to outline the principal components during chronic inflammation and the relation of these components to cancer initiation.