More than 20 years ago, an expansion of a B cell population characterized by the low expression of the complement receptor 2 (CD21) was discovered in peripheral blood of patients with HIV and common variable immunodeficiency (CVID) which is rare in healthy controls 1, 2. It took almost 10 years and multiple reports on ‘CD21low’ B cell accumulation in different human disease conditions including autoimmune and infectious diseases until the murine homolog of these cells has been identified in aged female and autoimmune-prone mice 3, 4. They were subsequently named age-associated B cells (ABCs). Despite some variance between ‘CD21low’ B cells in men and ABCs in mice [5], there was a strong resemblance between both B cell subsets including low expression levels of CD21 and high expression levels of the Th1 master transcription factor T-bet, the integrin CD11c and others 3, 4. In humans, these ‘atypical’ B cells comprise distinct subsets. In this review, we will focus on the human population with some references to the murine homolog.