Head and neck squamous cell carcinoma cells have the ability to spread along lymphatic channels to regional cervical lymph nodes. The pattern of spread of these cancer cells in the head and neck region has been well studied and is predictable. A sequential dissemination to cervical lymph nodes usually occurs and is almost always consistent. The negative impact of regional lymph node metastases on disease-specific survival cannot be over-emphasized (Figure 10.1) (1–16). While some head and neck cancer types tend to spread to regional lymph nodes at an early stage, others are associated with advanced primary tumor (Figure 10.2). Until recently, the acceptable rule of thumb was that spread of disease to regional lymph nodes decreases 5-year survival by approximately half. While this observation remains true for all mucosal cancers of the upper aerodigestive tract resulting from tobacco and alcohol abuse, in recent years, the human papillomavirus (HPV)-related oropharyngeal cancer epidemic has broken that rule. These HPV-positive tumors may present with bulky nodal disease and still carry a favorable prognosis regardless of treatment modality employed.