With the rapid development of nanotechnology as well as growing interest in immunotherapy, a great number of vaccine delivery vehicles have been explored in order to elicit potent adaptive immune responses against various infections or tumors. Recent studies have shown that targeting vaccine to antigen-presenting cells (APCs) within lymph nodes is an effective strategy for improving antigen-specific adaptive immune response. However, the characteristics of vaccine vehicles, such as size, surface charge and the degree of PEGylation, affect lymph node transfer and subsequent APC uptake, leading to different levels of immune responses. Thus, a comprehensive review of barriers, difficulties and corresponding strategies in lymph node targeting is important. In this review, we summarize the critical factors that affect lymph node delivery and survey recently reported successful vaccine carriers, which may be helpful for the rational design of vaccine vehicles.