The standard of care for cancer patients comprises more than one therapeutic agent. Treatment is complex since several drugs, administered by different routes, need to be coordinated, taking into consideration their side effects and mechanisms of resistance. Drug delivery systems (DDS), such as polymers and liposomes, are designed to improve the pharmacokinetics and efficacy of bioactive agents (drugs, proteins or oligonucleotides), while reducing systemic toxicity. Using DDS for co-delivery of several agents holds great potential since it targets simultaneously synergistic therapeutic agents increasing their selective accumulation at the tumor site and enhancing their activity allowing administration of lower doses of each agent, thus reducing their side effects. Taken together, implementation of smart DDS will hopefully result in increased patient's compliance and better outcome. This review will focus on the latest developments of combination therapy for cancer using DDS.