Dendritic cells (DCs) have the ability to elicit long-lasting antitumor immune responses. The immune system’s ability to produce an efficient immunological response depends on the presence of DCs at the anatomical site of the immune challenge. DCs transport antigens from the anatomical location of the immunological challenge to the draining lymph nodes, which are specialized immune organs where adaptive immunity is formed. Nowadays, the majority of anticancer DC vaccination clinical trials use monocyte-derived DCs (moDCs), and the progress made in understanding the biology of DCs, effector, and regulatory T cells has paved the way for the creation of new and innovative vaccine techniques. Since sufficient responsiveness of moDC-based cancer vaccination is still controversial in some malignancies especially multiple myeloma (MM), further studies needed to shed light in this regard. In this chapter, we aim to review the role of moDCs in the tumor microenvironment (TME) and its potential role in cross priming CD8+ T cells and inducing tumor immune responses.