Signaling through the MPAK happens in a dynamic fashion with signals transmitted from one component to the other until reaching the nucleus where modulation of the pattern of gene transcription takes place. Induction of different stresses causes phosphorylation cascade transmitted significantly through the p38 MAPKs. The main problem with defining the order of phosphorylation/dephosphorylation events that take place following p38 activation is the limited coverage of the dynamics of changes in the phosphoproteome. While not known for certain, the limited available data indicates that the phosphoproteome of eukaryotic cells comprises of many tens of thousands of phspho-sites and only a small fraction of these are detected in a routine phosphoproteomics analysis, even by one based on enrichment of the phosphopeptides with titanium oxide after strong cation exchange fractionation of the entire pool of tryptic digest of the proteome. Thus the obtained scheme of phosphorylation events is rather patchy and a full cascade view cannot be obtained this way. The main causes for such shortcoming relate to the failure of the mass spectrometers to fragment most of the phosphopeptides properly, so that they remain unidentified even though they were detected and fragmented in the mass spectrometer. The ways we attempt to overcome such shortcoming are through the use of SILAC or light/heavy nitrogen labeling and look for peptides (masses) that change in their signal intensities following treatment use targeted proteomics to identify and quantify these.