The immune system is a bona fide organ system comprising primary and secondary lymphoid tissues. This chapter provides a comprehensive overview of the anatomy and function of primary and secondary lymphoid tissues and considers their roles in both transplant rejection and tolerance. Primary lymphoid tissues are sites where T cells and B cells develop and mature, and mainly include the bone marrow and the thymus in mammals. Secondary lymphoid tissues are strategically located throughout the body at sites where antigen and antigen-presenting cells (APCs) are efficiently concentrated. The chapter focuses on lymph nodes, spleen, and Peyer's patches and discusses their direct relevance to solid organ transplantation. Tertiary lymphoid tissues, which are secondary lymphoid tissue-like structures that are induced at sites of chronic inflammation, are also be discussed as they are thought to influence allograft outcomes. The chapter highlights controversies and unresolved questions to encourage future investigations.