Axillary lymphadenopathy caused by the high immunogenicity of messenger RNA (mRNA) COVID-19 vaccines presents radiologists with new diagnostic dilemmas in differentiating vaccine-related benign reactive lymphadenopathy from that due to malignant causes. Understanding axillary anatomy and lymphatic drainage is key to radiologic evaluation of the axilla. US plays a critical role in evaluation and classification of axillary lymph nodes on the basis of their cortical and hilar morphology, which allows prediction of metastatic disease. Guidelines for evaluation and management of axillary lymphadenopathy continue to evolve as radiologists gain more experience with axillary lymphadenopathy related to COVID-19 vaccines. General guidelines recommend documenting vaccination dates and laterality and administering all vaccine doses contralateral to the site of primary malignancy whenever applicable. Guidelines also recommend against postponing imaging for urgent clinical indications or for treatment planning in patients with newly diagnosed breast cancer. Although conservative management approaches to axillary lymphadenopathy initially recommended universal short-interval imaging follow-up, updates to those approaches as well as risk-stratified approaches recommend interpreting lymphadenopathy in the context of both vaccination timing and the patient's overall risk of metastatic disease. Patients with active breast cancer in the pretreatment or peritreatment phase should be evaluated with standard imaging protocols regardless of vaccination status. Tissue sampling and multidisciplinary discussion remain useful in management of complex cases, including increasing lymphadenopathy at follow-up imaging, MRI evaluation of extent of disease, response to neoadjuvant treatment, and potentially confounding cases. An invited commentary by Weinstein is available online. ©RSNA, 2022.