C-type lectin receptors (CLRs) are a class of pathogen-recognition receptors that are actively investigated in the field of vaccine delivery. Many of their properties have functions linked to the immune system. These receptors are expressed abundantly on antigen-presenting cells and are considered to be the sentinels of immune surveillance owing to their endocytic nature and the ability to recognize a diverse range of pathogens through recognition of pathogen-associated molecular patterns. CLRs are also involved in the processes of antigen presentation mediated through the induction of dendritic cell maturation and cytokine production. These properties engender CLRs to be ideal for vaccine targeting. Conversely, CLRs also function to recognize glycosylated self-antigens to induce homeostatic control and tolerance. In this review, we will describe the various preclinical/clinical vaccination strategies to target antigens and plasmid DNA to this diverse class of receptors.