In immunogenetic studies, rapid and sensitive techniques for protein amino acid sequence analysis are needed. Methodologies involving mass spectrometry (MS) are a promising means to this end. A versatile and sensitive dipeptidyl peptidase approach using gas chromatography-mass spectroscopy (DP/GC-MS) has been developed that allows sequences of picomolar amounts of polypeptides to be determined from the peptide N- or C-terminus. Computer programs further enhance the procedure by simplifying data handling. The DP/GC-MS method has been utilized to determine partial C-terminal sequences for peptides derived from antibodies and from viruses. Using this information and incomplete sequence data from conventional N-terminal methods, final structural determinations were made. The DP/GC-MS method is currently being tested in studies on the structure of a 225 residue cyanogen bromide fragment from rabbit antibody heavy chain and the variable region of mouse hybridoma antibody heavy chains.