CD1d-restricted natural killer (NKT) cells are important contributors to antigen-specific antibody responses. There is, therefore, considerable interest in the design and implementation of strategies to appropriately activate NKT cells and boost vaccine-induced protective antibody responses. In order to achieve these goals, investigators are examining the mechanisms by which NKT cells enhance antibody responses. Although information is limited, it is now appreciated that both cognate and noncognate interactions between CD1d-expressing B cells and NKT cells drive enhanced antibody responses. NKT cells may provide B-cell help in the form of direct receptor-mediated interactions as well as by secretion of soluble effectors, including cytokines. In this article, we review the evidence in support of these mechanisms and discuss how they likely take place in the context of interactions of NKT cells with other cell types, such as dendritic cells and helper T cells. We also discuss the evidence that NKT cells affect discrete differentiation events in the multistep process by which a naive B cell experiences antigen and develops into a memory B cell or an antibody-secreting plasma cell. Since most information on NKT cells and humoral immunity has been derived from murine studies, we discuss what is known about human NKT cells and humoral immunity. We offer thoughts on whether the findings in murine systems will translate to humans.