The standard interface of pianos, organs, and other keyboard instruments, with its pattern of twelve interlocking keys, is a compromise by design. The twelvefold division of the scale into fixed pitches has both shaped and served Western music since medieval times. Yet the notes of this scale form pitch relationships that, for the most part, only approximate the intervals of the natural harmonic series. Over the centuries, scientists, inventors, instrument makers, composers, and musicians have explored myriad ways of accommodating and even overcoming this discrepancy. One strategy for mitigating the limitations of the standard keyboard’s twelve-tone octaves has been to add extra notes to create within the keyboard’s scale microtonal divisions, or intervals smaller than a semitone (the distance between two adjacent notes on the piano). Consideration of some notable early modern examples of microtonal keyboards, including those associated with Nicola Vicentino and Gioseffo Zarlino, can help to contextualize later developments in the nineteenth and twentieth centuries, when microtonal instruments served a variety of aesthetic, philosophical, and scientific ends.