5-fluorouracil is a widely used chemotherapeutic agent. Its role and activity in the treatment of squamous cell carcinoma of the head and neck are reviewed. In head and neck cancer, 5-fluorouracil is mostly used in combination with cisplatin. Despite a high activity of this regimen, as documented in response rates of up to 90%, its use as an adjuvant to surgery and radiation does not impact consistently on survival rates. In contrast, 5-FU-based chemotherapy with concomitant radiotherapy seems to improve treatment outcome. Several randomized trials suggest improved locoregional control with concomitant chemoradiotherapy with a 5-fluorouracil-based chemotherapy regimen. The activity and the metabolism of 5-FU can be further modulated by cisplatin, hydroxyurea, and leucovorin.