Anti-citrullinated protein antibodies are primarily associated with a progressive course in the autoimmune disease rheumatoid arthritis, a disease with a chronic and inflammatory nature. These antibodies do not appear to have any strict dependency for reactivity except from the presence of the non-genetically encoded amino acid citrulline, which is the result of a posttranslational modification, catalyzed by calcium-dependent peptidylarginine deiminase enzymes. Nevertheless, several amino acids surrounding the citrulline residue notably influence antibody reactivity, especially with a central-Cit-Gly-motif being essential for antibody reactivity. Most importantly, these antibodies have been proposed to be divided into two groups, based on their ability to recognize multiple citrullinated peptides. Thus, an “overlapping” antibody group, which appears to recognize several citrullinated peptides, and a “non-overlapping” antibody group, which only recognizes a limited number of citrullinated peptides, have been proposed. Based on these findings, we suggest that antibodies recognizing several citrullinated targets, also referred to as cross-reactive antibodies, primarily are backbone-dependent, whereas less cross-reactive antibodies primarily depend on the side chains of the amino acids comprising the epitopes for stable antibody-antigen interactions, which reduces the degree of cross-reactivity significantly. Clarifying the reactivity pattern of anti-citrullinated protein antibodies may contribute to determining their true nature of origin.