The tumor microenvironment (TME) plays an important role in the development and progression of cancer and has been shown to contribute to resistance to therapy. Inflammation is one of the hallmarks of cancer implicated in disease phenotype. Therefore, understanding the mechanisms that regulate inflammation in cancer and consequently how inflammatory mediators promote cancer progression is important for our understanding of cancer cell biology. The transcription factor GLI2 was initially identified as a member of the Hedgehog (HH) signaling pathway. During the last decade, studies have shown a novel mechanism of GLI2 regulation independent of HH signaling, where GLI2 consequently modulated several cytokine genes in the TME. These studies highlight a novel role for GLI2 as an inflammatory mediatory independent of HH stimulation. This chapter will discuss canonical and noncanonical pathways of GLI2 regulation and some of the downstream cytokine target genes regulated by GLI2.