The discovery of Toll-like receptors (TLRs), and their role in sensing infections represents one of the most seminal advances in immunology in recent years. It is now clear that TLRs play a fundamental role in innate recognition of microbes, and stimulate and tune the quality of the adaptive immune response. However, major knowledge gaps remain in our understanding of how TLRs regulate the development and persistence of T- and B-cell memory. Here, we review our current understanding of how TLR-signaling shapes the adaptive immune response, and highlight unanswered questions, the solution of which will be imperative in the rational exploitation of TLRs in vaccine design and immune therapy.