Background <p>Brain metastases (BM) represent a deleterious complication in many solid tumors. Despite advances in systemic therapy, BM are still associated with significant morbidity and mortality. Consequently, preventive strategies are gaining importance and represent a dynamic area of investigation.</p> Methods <p>Relevant literature and clinical trials were included, focusing on systemic therapies, multimodal treatment approaches, and future therapeutic avenues. Clinical trials reporting on secondary (preventing BM in a yet BM-free cancer patient) and tertiary prevention (preventing formation of new and recurrence of existent BM in a patient who has already developed BM) were included.</p> Results <p>A number of BM treatment-effective drugs have shown BM-preventive effects: In NSCLC, the EGFR-inhibitor osimertinib and ALK inhibitors like alectinib, brigatinib and lorlatinib lower the incidence of BM. In HER2-positive breast cancer, tucatinib and trastuzumab deruxtecan have preventive activity in patients without BM at baseline. In melanoma, BRAF/MEK inhibition and immunotherapy might be able to delay the onset of BM, although prospective data remains limited to date. Notably, drugs effective in BM therapy do not necessarily work in BM prevention, and vice versa. Preclinical data, including insights from Cancer Neuroscience, reveal novel preventive strategies warranting further exploration.</p> Conclusions <p>Preventive strategies against BM in solid tumors are feasible, though data are sparse at this time. Preventing BM requires a personalized, multidisciplinary approach, integrating tumor biology, individual risk assessment, and therapeutic advances. Secondary prevention in patients with BM is as vital as tertiary prevention, warranting prospective validation of preclinical concepts.</p>