Dendritic cells (DCs) are versatile elements of the immune system and are best known for their unparalleled ability to initiate and modulate adaptive immune responses. During the past few decades, DCs have been the subject of numerous studies seeking new immunotherapeutic strategies against cancer. Despite the initial enthusiasm, disappointing results from early studies raised some doubts regarding the true clinical value of these approaches. However, our expanding knowledge of DC immunobiology and the definition of the optimal characteristics for antitumor immune responses have allowed a more rational development of DC-based immunotherapies in recent years. Here, after a brief overview of DC immunobiology, we sought to systematize the knowledge provided by 20 years of clinical trials, with a special emphasis on the diversity of approaches used to manipulate DCs and their consequent impact on vaccine effectiveness. We also address how new therapeutic concepts, namely the combination of DC vaccines with other anticancer therapies, are being implemented and are leveraging clinical outcomes. Finally, optimization strategies, new insights, and future perspectives on the field are also highlighted.