Lipopolysaccharide (LPS) is a natural adjuvant synthesized by gram-negative bacteria that has profound effects on CD4 T-cell responses. LPS stimulates cells through the Toll-like receptor 4 (TLR4), causing the release of inflammatory cytokines and upregulation of costimulatory molecules on antigen-presenting cells (APCs). The combination of signals from antigens, costimulation, and cytokines allows CD4 T cells to overcome suppressive barriers and accumulate in large numbers. T cells that are primed in an LPS-stimulated environment are programmed for long-term survival following clonal expansion. LPS is well-known for generating Th1 responses. However, under appropriate conditions it can also support differentiation into other T-helper lineages, demonstrating its pleiotropic nature. Although molecular analyses have provided insights into how immune responses are controlled by LPS in vivo, its powerful adjuvant activity is also associated with toxicity. Research on partial TLR4 agonists such as monophosphoryl lipid A have demonstrated that toxicity and immunogenicity are not always linked, making them useful candidates for human vaccines. In this sense, many years of LPS research have ultimately contributed to vaccine design, and the next generation may involve studying how the balance between different CD4 T-cell subsets is controlled.