The antigenic variability of the M protein is attributable to selective immune pressure. However, within this variability, functional conservation also seems to be at play, as sequences vary among M types but are stable within the type. With >220 M types, it is difficult to imagine an equivalent number of functionally indispensable host factors with which M protein variable regions interact. Recent structural studies examining the interaction of four M protein HVRs with human C4b-binding protein (C4BP) offer an answer to this puzzle. These structures revealed that the α-helical coiled coils of the four M protein HVRs present a pattern of amino acids that are chemically complementary to a uniform and tolerant ‘reading head’ present on C4BP. Significantly, the C4BP-binding sequence pattern identified in the four structurally characterized M protein HVRs were found to be conserved among a much larger set of M protein HVRs. This conserved sequence pattern appears to be masked from immune recognition by diversion. The large number of variable amino acids surrounding the C4BP-binding pattern appears to divert the attention of the antibody response, resulting in a type-specific rather than a type-promiscuous response. However, suggestive evidence exists that certain antibodies can mimic the M type-promiscuous binding mode of C4BP, thereby providing broad neutralization. These results show that hidden within M protein variability are sequence patterns conserved for interaction with indispensable host factors.