Historically, axillary lymph node dissection was considered necessary for regional control of breast cancer. Moreover, nodal status was the major determinant of the need for chemotherapy. The increased use of systemic therapy coupled with expanding indications for nodal irradiation has led to interest in optimizing patient outcomes by leveraging the local control benefits of radiotherapy and systemic therapy to decrease the extent of surgery. A series of landmark surgical and radiotherapeutic trials has demonstrated low rates of disease recurrence with concomitant improvements in treatment-associated lymphedema and quality of life with the use of sentinel node biopsy and nodal irradiation as opposed to complete axillary dissection in the management of node positive breast cancer. This chapter will explore the evolution of regional nodal management, culminating in current approaches to tailored patient selection for axillary lymph node dissection, sentinel lymph node biopsy, and adjuvant regional nodal irradiation.