Agents with mechanisms novel to breast cancer care have been approved to treat breast cancer. These agents include drugs that target cyclin-dependent kinases, phosphoinositide 3-kinase PI3KCA gene mutations, PARP, checkpoint regulation, and novel antibody-drug conjugates. However, these novel approaches bring a risk of toxicities quite different from those of conventional cytotoxic chemotherapy. Here, we review these agents and discuss related adverse events, with particular attention to endocrine, pulmonary, and dermatologic toxicities. Endocrine toxicities associated with novel cancer therapies for breast cancer are distinct and often present with symptoms related to the specific hormonal deficiencies and rarely hormonal excess. Given the complex and sometimes irreversible nature of these toxicities, once recognized, transdisciplinary management with an endocrinologist experienced with managing drug-related toxicities is encouraged. Drug-related pneumonitis is a serious concern with new targeted therapies. Presentation may not be easily distinguished, and a multidisciplinary team approach can optimize patient care. Heightened awareness is crucial for early detection and treatment. Management should follow recommendations provided by the National Cancer Institute Common Terminology Criteria for Adverse Events and agent-specific guidelines. Cutaneous toxicities from anticancer therapies represent a common and often poorly characterized challenge for patients with breast cancer. Although our understanding of dermatologic effects from novel therapies continues to improve, the breadth of toxicities spans all dermatologic conditions. Targeted therapies offer effective and often novel therapeutic strategies for patients with breast cancer but also bring new adverse event profiles. In this era, it will be important both to closely follow monitoring recommendations and to remain vigilant for emerging toxicities.