Diffuse mucosal premalignant changes and multifocal squamous cell carcinoma present unique clinical challenges for the otolaryngologist and can be distressing to patients. In this program, conditions that predispose patients to diffuse malignant/premalignant changes and the management of those conditions will be reviewed. This panel will present practical, stepwise approaches to diffuse premalignant lesions and multifocal malignancy, including novel strategies and a discussion of challenging cases. Oral lichen planus (OLP) and Proliferative Verrucous Leukoplakia (PVL) are an inflammatory conditions that can predispose wide areas of the oral mucosa to malignant transformation. The possible etiologies, differential diagnoses, the spectrum of presenting findings, clinical course, management strategies and emerging therapeutics will be reviewed. In addition to OLP and PVL, other causative and potentially modifiable factors will be discussed, including the role of dental products/materials. The natural evolution of these conditions may result in multifocal disease. When broad areas of the oral mucosa demonstrate high grade premalignant changes or multifocal transformation, the role of surgery may be limited. A practical approach to multifocal or diffuse mucosal premalignant and malignant changes will be presented. The indications and outcomes of wide local excision and laser ablation as surgical management tools will be reviewed. The panelists will discuss when it may be appropriate to refer the patient for consideration of radiation and/or systemic therapy.