Glioblastoma multiforme is one of the most widespread and dangerous forms of brain tumor with high inflammation. The tumor microenvironment comprises diverse tumor cells, different types of immune cells, and the extracellular matrix. Inflammatory mediators like chemokines, cytokines, and growth factors possibly serve as a capable therapeutic target to quash their tumor-promoting properties in glioblastoma multiforme (GBM). Cytokines are a heterogeneous group of soluble functional proteins which are also associated with the induction and progression of tumors. These are supposed to have both pro-inflammatory (such as tumor necrosis factor-α (TNF-α), interleukin-17A (IL-17A), interferon-γ (IFN-γ), IL-4, IL-2, IL-6, IL-12, IL-13) and anti-inflammatory (such as transforming growth factor-β (TGF-β), IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF)) actions and are the crucial communications channels in the tumor microenvironment. In the present minireview we discuss the tumor microenvironment and inflammatory mediators and focus on the involvement of cytokines in establishing communication with the tumor microenvironment. The presented data highlight the possible roles of cytokines in communication between glioblastoma cells and tumor microenvironment. Cytokines formed by immune cells protect the host organs while cytokines secreted by tumor cells are used for their advantage. Though the clinical trials with a number of immunotherapeutic agents are going on around the globe, there is still a requirement for thorough investigation of the regulatory mechanism managing GBM growth, recurrence, and tumor response to the therapy.