The concept of molecular mimicry describes situations in which antigen sharing between parasites and hosts could benefit pathogen evasion from host immune responses. However, antigen sharing can generate host responses to parasite-derived self-like peptides, triggering autoimmunity. Since its conception, molecular mimicry and the consequent potential cross-reactivity following infections have been repeatedly described in humans, raising increasing interest among immunologists. Here, we reviewed this concept focusing on the challenge of maintaining host immune tolerance to self-components in parasitic diseases. We focused on the studies that used genomics and bioinformatics to estimate the extent of antigen sharing between proteomes of different organisms. In addition, we comparatively analyzed human and murine proteomes for peptide sharing with proteomes of pathogenic and non-pathogenic organisms. We conclude that, although the amount of antigenic sharing between hosts and both pathogenic and non-pathogenic parasites and bacteria is massive, the degree of this antigen sharing is not related to pathogenicity or virulence. In addition, because the development of autoimmunity in response to infections by microorganisms endowed with cross-reacting antigens is rare, we conclude that molecular mimicry by itself is not a sufficient factor to disrupt intact self-tolerance mechanisms.