Literature reports often tout the superior resolution, sensitivity, and mass-accuracy capabilities of Fourier transform mass spectrometry (FTMS). These claims are indeed true for ions of mass-to-charge ratios (m/z) less than a few thousand. The organic mass spectrometry literature is replete with examples of the utility and importance of FTMS for the elucidation of ion-molecule reaction pathways and kinetics. On the other hand, a review of the biological mass spectrometry literature demonstrates that FTMS is seldom employed for biological applications. The absence of FTMS applications in the biological literature has been, in part, due to the inability to realize the potential of the technique for ions of high m/z, such as those produced by matrix-assisted laser desorption (MALD) (1). We expect, however, that applications of FTMS coupled with electrospray ionization (ESI) will multiply rapidly, owing to the high resolving power that can be achieved for multiply-charged ions on the order of m/z 1000, as demonstrated by an average mass-resolving power of 63,000 for the multiply-charged states of equine cytochrome c (MW 12352) as shown in Fig. 1 (2). The purpose of this article is to introduce the reader to the issues that hinder the development of routine high mass-to-charge FTMS and to the recent advances and strategies that are extending the impressive capabilities realized for low mass-to-charge (<2000) organic molecules to high mass-to-charge biological molecules. Our intentions do not include, however, providing a review of ESI or the other applications of FTMS to biological molecules. (C) 1995 John Wiley & Sons, Inc.