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Tumor resistance and low drug efficacy prompt to investigate new therapeutic strategies that have high efficacy and low toxicity, especially for cancers with poor prognosis. This goal has been recently achieved using particular pharmaceutical combination or nanotechnologies to specifically deliver drugs at the tumor site. Novel combined treatments employ either naturally active ingredients or drugs already intended for other uses, with the aim to increase cell sensitivity to therapy and reduce drug toxicity. Combined treatments usually improve the overall therapeutic efficacy of the single drug. Drug-drug interactions allow synergistic effects. Several evidences indicate that synergy can be affected by drug-drug ratio and drug administration order. Therapeutic efficacy can be enhanced through drug entrapment in nanocarriers that allow a site-specific targeting, resulting in a build-up of the drug in the tumor with a significant toxicity reduction. Several studies investigated combined entrapment of two or more drugs each one characterized by different mechanisms of action. These nanosystems improve synergistic efficacy and could be a device to resolve toxicity and multi-drug resistance. Nano-encapsulation of anticancer agents by targeting specific tumor tissues significantly optimizes drug bioavailability, biocompatibility and therapeutic efficacy. The efficacy of these formulations results from receptor-mediated endocytosis and prolonged circulation time. Drug encapsulation also allows using limited final concentration while avoiding its activity within the blood circulation. In this review we report recent findings about novel combined treatment focusing on synergistic effects and mechanisms of action. We will also overview the latest drug delivery system and their therapeutic benefits in cancer treatment.