The activation of classical C pathway by immune complexes depends on the binding and activation of C1, the first component of C. The Ig in the complex must be of the right class and in the right configuration to accomplish the conversion of precursor (zymogen) C1s to C1s, the active enzyme, whose substrates are C4 and C2. The primary question discussed in this paper is evidence that indicates that epitope distribution and density is a major factor in controlling the configuration of antibodies which in turn controls the activation of bound C1. This evidence confirms earlier findings that binding of C1 is a necessary but not sufficient condition for activating C1.