Although proteomics has rapidly developed in the past decade, researchers are still in the early stage of exploring the world of complex proteoforms, which are protein products with various primary structure alterations resulting from gene mutations, alternative splicing, post-translational modifications, and other biological processes. Proteoform identification is essential to mapping proteoforms to their biological functions as well as discovering novel proteoforms and new protein functions. Top-down mass spectrometry is the method of choice for identifying complex proteoforms because it provides a “bird's eye view” of intact proteoforms. Fragment ion series in top-down tandem mass spectra provide essential information for identifying primary sequence alterations in proteoforms. Extended proteoform databases and spectral alignment are the two main approaches for proteoform identification. However, due to the combinatorial explosion of various alterations on a protein and the limitations of available spectral alignment algorithms, the proteoform identification problem has still not been fully solved.