Pathogen recognition by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation and the initiation of adaptive immunity. Recent studies have shown that innate lymphocytes—natural killer (NK), natural killer T (NKT), and γδ T cells—also trigger DC maturation. This interaction in turn expands and activates innate lymphocytes and initiates adaptive T cell immunity. Here, we comment on the evidence that these pathways are TLR independent and have the potential to respond to infection, malignancy, and immunotherapy.