It is crucial for the immune system to minimise the number of circulating mature self-reactive B cells, in order to reduce the potential for the development of autoantibody-related autoimmune diseases. Studies of animal models have identified two major checkpoints that ensure that such cells do not contribute to the naïve B cell repertoire. The first is in the bone marrow as B cells develop and the second is in the spleen; B cells that are released from the bone marrow as transitional B cells go through more stringent selection in the spleen before they develop into mature naïve B cells. Transitional B cells and their maturation have mostly been studied in mice. However, recent studies characterised human transitional B cells and found considerable differences to current models. In this review, we will consider these differences alongside known differences in mouse and human splenic function and ask whether human transitional B cells might develop along a different pathway.