Monoclonal antibodies (MAB), particularly those recognizing the epidermal growth factor receptor family (HER, EGFR, or ERBB), have multiple applications in oncology. These biotechnological products have high specificity and affinity for their target. However, due to their functional and structural complexities, low tissue distribution, antigen (HER) burden, body weight of patients, and immunogenicity, they are characterized by high pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. These inherent challenges in the PK and PD behavior of anti-HER MAB need to be overcome to develop more effective therapies and optimize the available ones. In particular, adequate dosing strategies are required to improve patients’ quality of life. The objectives of this publication are to describe the main anti-HER MAB physicochemical and PK properties and compare them to those of small molecule drugs. In addition, the PK of different MAB —classified based on the origin (chimeric, humanized, or fully human), and that recognizes other members of the HER family (HER1, HER2, and HER3) over-expressed in tumors of epithelial origin— is presented. This information allows us to understand the essential role of PK in supporting optimal dosing strategies of anti-HER MAB.