Proteins are the primary effectors of function in biology, and thus, complete 
knowledge of their structure and properties is fundamental to deciphering 
function in basic and translational research. The chemical diversity of proteins 
is expressed in their many proteoforms, which result from combinations of 
genetic polymorphisms, RNA splice variants, and posttranslational modifications. 
This knowledge is foundational for the biological complexes and networks that 
control biology yet remains largely unknown. We propose here an ambitious 
initiative to define the human proteome, that is, to generate a definitive 
reference set of the proteoforms produced from the genome. Several examples of 
the power and importance of proteoform-level knowledge in disease-based research 
are presented along with a call for improved technologies in a two-pronged 
strategy to the Human Proteoform Project.