Squamous cell carcinomas of the head and neck (SCCHN) are one of the two most common human cancers. Most patients present with disease that is incurable or likely to fail conventional therapy. Unacceptable functional and cosmetic deficits occur in many when cured with surgery and/or radiotherapy. Effective cytotoxic therapy has the potential to cure patients with advanced disease (induction trials), reduce the undesirable consequences of conventional therapy (organ preservation trials) and prevent recurrences following conventional therapy (adjuvant trials). Cytotoxic therapy has shown such potential only when microscopic disease is eradicated. Clinical trials are hampered by widely different cytotoxic responses or clinical outcomes following conventional therapy in patients with similar clinical characteristics and amount of disease. Attempts to predict the clinical outcome of individual patients on the basis of differences in clinical or morphological parameters have not been successful. Flow cytometric measurements of cellular DNA content have been associated with prognostic differences in many human malignancies. Comparisons of DNA ploidy in recurrent and previously untreated patients as well as serial measurements in advanced patients undergoing cytotoxic therapy indicate that patients with diploid tumors or significant subpopulations do not achieve microscopic eradication of tumor. In advanced patients undergoing surgery as initial therapy, advantages in recurrence rates, disease free survival and absolute survival have been associated with diploid tumors. Significant differences in the histological patterns if tumor growth and stromal interface for diploid and aneuploid tumors have been demonstrated and may account for the differences in local-regional relapse rates following surgery. The interpretation and clinical application of these findings is difficult and incomplete, particularly for diploid tumors or components of mixed tumors, without further characterization of these ploidy groups by multi-parameter flow cytometry. The determination of cellular DNA content parameters may aid in the prediction of clinical outcome and indicate mechanisms underlying response and resistance in patients with advanced SCCHN.