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Cancer cells weakened the anti-proliferative nature of chemotherapeutics by mounting molecular, physiological, and enzymatic resistance mechanisms against not only the previously treated drug but also to the structurally different anticancer drugs, a phenomenon termed as multidrug resistance (MDR). Pioneering strategies such as synthesizing new molecules, refurbishing the existing anti-proliferative agents, combinatorial approach, and nanotechnology are considered as advantageous in curbing MDR. However, nanotechnology remarkably evident as the first-class endeavor due to the nano size, ability to transport the range of payloads, improved stability, and solubility, prolonged action, targeted to specific components of cancer cells. Nonetheless, peptide-functionalized or peptide nanosystems tenders more benefits, particularly reinforcing and synergizing the activity of anti-proliferative agents, precise recognition of both cancer cells and its resistant counterparts, possessing high affinity to the highly expressed specific receptors in MDR cancer cells, etc. This chapter sheds light on the advantages of peptide-nanosystems for overriding MDR.