Targeted inhibition of epidermal growth factor receptors (EGFR) is becoming a standard anticancer treatment in defined clinical scenarios. EGFR inhibition may be achieved either by small-molecule orally bioavailable tyrosine kinase inhibitors, such as gefitinib or erlotinib, or else by large-molecule receptor antibodies, such as cetuximab or panitumumab. Here, we describe a case of pancreatic cancer in which the small-molecule EGFR antagonist erlotinib was used before and after the EGFR antibody cetuximab, with unexpected potentiation of both toxic and therapeutic sequelae.