Neck masses are common in the outpatient setting. Although the differential diagnosis is broad, 95% of neck masses are benign. Efficiently identifying malignant masses is a priority. An investigatory framework allows for accurate diagnosis without delays in care. Human papillomavirus–related oropharyngeal squamous cell carcinoma constitutes approximately 70% of new head and neck cancer diagnoses. The differential diagnosis of a neck mass can be divided into three categories based on acuity: acute (eg, infection), subacute (eg, malignancy), and chronic (eg, congenital, thyroid). When a diagnosis cannot be made by history, risk factors, and physical examination alone, imaging or biopsy is indicated. Contrast-enhanced computed tomography is recommended for most nonpulsatile, nonthyroid masses. For thyroid masses, ultrasonography is the imaging modality of choice. Contrast-enhanced magnetic resonance imaging, computed tomography angiography, and positron emission tomography are preferred in cases of cranial nerve involvement, pulsatile masses, and potential metastases, respectively. When biopsy is indicated, fine-needle aspiration is recommended. In the detection of malignancy, fine-needle aspiration has an accuracy of 93%, sensitivity of 90%, and specificity of 97%, regardless of anatomic site.