Gastrointestinal side effects such as diarrhea are frequent and occur in most cases during the first days of treatment. Management of diarrhea is recommended to be handled similar to chemotherapy-induced diarrhea based on loperamide and octreotide as presented in this review. Relief for stomatitis/mucositis can be provided with effective topical care and cooling. Rash and dermatitis warrant specific topical and/or oral antibiotics in combination with local care, depending on the severity. Fatigue is infrequent under afatinib, but, if present, should be taken seriously.