The formation and progression of head and neck squamous cell carcinoma (HNSCC) is multisystemic and involves the immune system, vascularization, and dissemination. Immune involvement includes the subversion of anti-tumor defenses. Vascularization involves both angiogenesis and vasculogenesis. Dissemination involves local tumor invasion as well as distant metastasis through processes including angiogenesis and lymphangiogenesis. Current studies in the dysregulation of various processes, including genetic stability, angiogenesis, lymphangiogenesis, immune regulation, and immune function, are opening opportunities for the development of targeted tumor therapies. The interrelationship of these processes in HNSCC development will be explored in this review.