Mass spectrometry (MS) is rapidly becoming an indispensable tool for the 
analysis of posttranslational modifications (PTMs) of proteins, and particularly 
histone PTMs that regulate physiological processes. The more traditional 
bottom-up approach of searching for modifications on peptides rather than intact 
proteins (top-down) has proven useful for finding phosphorylation, acetylation, 
and ubiquitination sites. With the use of modern instrumentation and various 
MS-based techniques, peptides and their PTMs can be characterized in a 
high-throughput manner while still maintaining high sensitivity and specificity. 
In complement to bottom-up MS, recent advances in MS technology, such as 
high-field Fourier transform ion cyclotron resonance (FTICR)-mass spectrometry, 
have permitted the study of intact proteins and their modifications. On-line and 
off-line protein separation instruments coupled to FTICR-MS allow the 
characterization of PTMs previously undetectable with bottom-up approaches. The 
use of unique fragmentation techniques in FTICR-MS provides a viable option for 
the study of labile modifications. In this chapter, we provide a detailed 
description of the analytical tools - mass spectrometry in particular - that are 
used to characterize modifications on peptides and proteins. We also examine the 
applicability of these mass spectrometric techniques to the study of PTMs on 
histones via both the bottom-up and top-down proteomics approaches.