Background: Breast cancer is the most common cancer and the leading cause of cancer death in women. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with primary breast cancer have recurrent disease. The rates of local and systemic recurrence vary within different studies, but distant recurrences are dominant. In order to offer more effective and less toxic treatment, the selection of therapies requires considering the clinical and molecular characteristics of the tumor. Nowadays, systemic treatment of breast cancer includes cytotoxic, hormonal and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of cases with metastases. However, after a variable period of time, progression occurs. So, resistance to therapy is not only common, but also expected. The aim of this article was to review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein, emergence of refractory tumors associated with multiple resistance mechanisms and resistance factors characteristic to host-tumor-drug interactions. The most important anticancer agents specific to breast cancer are described. Conclusions: In spite of multiple studies and different schemes of chemotherapy, 30% of patients with early diagnosed mammary carcinomas develop recurrences during disease history. The majority of recurrences are developing in cases with lymph node metastases. Treatment resistance is caused by multiple factors, is frequently unforeseeable and the most important reason of its development is existence of multiple subtypes of breast carcinoma.