Background: Trastuzumab–deruxtecan (T-DXd), a new-generation antibody drug conjugate, has greatly improved the survival and clinical benefit rates of patients affected by advanced HER2-positive/HER2-low breast cancer according to the results of controlled clinical trials with a manageable safety profile. Data from randomized clinical trials can provide valuable information for the management of patients in everyday clinical practice, including those who would typically be excluded from such trials due to not meeting the inclusion criteria. Methods: In this narrative review, we describe and discuss real-world studies in the literature on the use of T-Dxd in HER2-positive and HER2-low MBC patients, providing a critical analysis of the specific settings of clinical interest. Results: Using a PubMed search, we identified nine real-world studies on T-DXd that are available in the literature. A total of 7146 patients have been included in these retrospective studies. A total of 5/9 studies also included HER2-low MBC patients. In the majority of cases, patients had high disease burden with lung and liver involvement. We then reviewed and discussed clinical areas of interest, including heavily pretreated patients, poor performance status, HER2-positive versus HER2-low disease, brain metastasis, elderly patients, lung toxicity, safety profile, and dose modifications. Conclusions: Our analysis confirms the activity of the drug described in real-world studies and shows a favorable safety profile, with manageable adverse effects.