Anti-C1q autoantibodies can be found in the sera of patients with several autoimmune diseases, but also in healthy individuals. Although these anti-C1q autoantibodies were already identified several decades ago, they still puzzle both immunologists and nephrologists. The main reason for this puzzling effect are observations that seemed to indicate quite clearly that anti-C1q should be pathogenic to the kidney and the observation on the other hand that anti-C1q autoantibodies can be found in several disease conditions, as well as in healthy individuals, and are then unrelated to overt renal inflammation. This puzzle is the focus of the current review, which will provide an overview of the historical data, define the clinical interests and, importantly, will try to put several aspects in perspective based on recent observations in patients and in murine models. In addition, the paper will discuss therapeutic intervention possibilities regarding anti-C1q-mediated damage in systemic lupus erythematosus, as well as the therapeutic potential of anti-C1q antibodies in other conditions.