Microbes populated the earth long before any eukariotic cell. Therefore, in order to survive, mono and multi-cellular organisms had to develop mechanisms of adaptation, cohabitation and defense against bacteria, fungi and viruses. One of these mechanisms is mediated by immunoglobulins in the serum and at mucosal surfaces. B cells and their antibodies, both natural and adaptive, play a fundamental role in the immediate and late defence against microbes and in the control of the commensal microflora. They also protect the organism from viruses neutralizing them before infection. Therefore, although over the last years B cells have been considered the mere executors of the orders derived by the complex interaction between antigen presenting cells and T cells, new attention is concentrating on the humoral response. For example, B cells are now the cellular target of a new generation of vaccines against HIV, the best known T cell virus. It has been found that B cells sense the environment not only through their unique B cell receptor, but also using the more promiscuous and evolutionary ancient TLRs. This mode of recognition does not need T cells, but efficiently induces B cell activation and differentiation.