Successful management of patients with lesions of oral mucosa can be accomplished by dental health care providers if a step-by-step approach is used to gather information and apply it in a systematic manner to diagnostic decision trees. This course provides general guidelines that can be used to eliminate or exclude most oral lesions from the clinical differential diagnosis. Those lesions that cannot be excluded constitute the clinical differential diagnosis. The value of formulating a clinical differential diagnosis for an oral lesion is that it eliminates guessing at the best diagnosis and thus guides the next steps in managing the patient’s lesion. Determining the definitive or final diagnosis of an oral lesion often requires additional testing, such as obtaining a biopsy specimen and having it microscopically diagnosed.