Head and neck squamous cell cancer (HNSCC) is one of the most common tumors worldwide and there is an enormous need for innovative therapy approaches. Several recent studies suggest tumor entity specific roles of glycogen synthase kinase 3 (GSK3) in different human cancers, acting as tumor suppressor or as tumor promoter. Here we describe the role of GSK3 with respect to different parameters within HNSCC progression.Base line expression and activity profiles of p-GSK3α/β (Ser21/9) and p-GSK3α/β (Tyr279/216) were analyzed by immunohistochemistry and western blotting. Four different permanent HNSCC cell lines were exposed to the potent GSK3α/β inhibitor SB 216763. Cell viability was controlled via the MTT test. Cell migration was quantified with the Real Time Cell Analyzer (RCTA) xCELLigence. Regulation of the epithelial-mesenchymal transition (EMT) was measured with the Human Epithelial to Mesenchymal Transition (EMT) RT2 Profiler™ PCR Array and scratch assays. Taqman probes were used to detect the specific gene expression profiles of inflammatory cytokines Interleukin IL1β, IL6, IL8, IL10, TNFα and IFNβ.Exposure of permanent HNSCC cell lines to the specific GSK3α/β inhibitor SB 216763 leads to significant growth inhibition, inhibition of migration and decreased levels of active GSK3α/β in a dose dependent manner.Exposure of HNSCC lines to SB 216763 also resulted in a markable shift of EMT markers and functional EMT dysregulation. Functionally GSK3 differentially mediates the expression of TLR4- and TLR3-induced inflammatory cytokines in HNSCC, whereas no effect of SB 216763 on the NFkB activity was noticed.GSK3α/β plays a crucial role in a variety of regulatory networks for HNSCC cancer progression as it drives proliferation or migration and thus GSK3 could serve as an interesting target for clinical drug development.