Clinical use of the 7-valent pneumococcal protein conjugate (PCV7) vaccine, which includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, dramatically reduced invasive pneumococcal disease (IPD); however, the effectiveness was diminished due to serotype shift. Although shift due to known serotypes was anticipated, shift by misidentified serotypes was unexpected. We describe the experience with newly recognized serotypes 6C and 6D, which were mistyped as serotypes 6A and 6B, respectively. Although serotype 6D caused only occasional infections, IPD due to serotype 6C disease expanded in the PCV7 era. Subsequent studies showed that PCV7 provided cross-protection against serotype 6A but not serotype 6C. The 13-valent pneumococcal protein conjugate (PCV13) vaccine, which includes PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F, 19A, may provide protection against IPD due to serotypes 6C and 6D. Regardless, this narrative illustrates the potential impact of unrecognized serotypes on the efficacy of a serotype-specific vaccine.