Dendritic cells (DCs) are the immune system headquarter with outstanding capabilities in initiating, linking, and directing immune responses with providing four special signals (specific recognition, co-stimulation, polarization, and homing), so they would be the best mean to manipulate the immune system to get rid of many complicated diseases as well as cancers. After around 50 years of discovery and 25 years of being applied in clinical trials, DC-based cancer immunotherapy has shown that it is safe and reliable but has to become more and more elaborated to achieve an ideal clinical response. A wide range of strategies has been tested for taking DCs into the clinic including in vivo targeting and enhancing approaches, ex vivo expansion along with antigen loading and genetic modification strategies, and novel innovating methods in using naturally occurring DC subsets. There are more than 430 registered clinical trials so far mostly about melanoma that 19 of them have reached phase III. Top challenges in this field go around the best mixture or DCs to be targeted or expanded and how to offer them the capability to overwhelm the highly immunosuppressive tumor microenvironment using cutting-edge nano-biomolecular engineering tools and the best-matched combination therapies. The future of this interesting immunology field will probably rely on a super-personalized approach in which each patient receives a certain type of engineered DCs with specific timing and complementary treatment.