Mass spectrometry based proteomics has become the method of choice for pinpointing and monitoring thousands of post-translational modifications, predominately phosphorylation sites, in cellular signaling studies. Critical for achieving this analytical depth is the enrichment of phosphorylated peptides prior to liquid chromatography-mass spectrometry (MS) analysis. Despite the high prevalence of this modification, the numbers of identified phosphopeptides lag behind those achieved for unmodified peptides, and the cause for this still remains controversial. Here, we use an effective phosphatase protocol that considerably improves global ionization efficiency and, therefore, the overall sensitivity and coverage of standard phosphoproteomics studies. We demonstrate the power of our method on the model system of Salmonella-infected macrophages by extending the current quantitative picture of immune signaling pathways involved in infection. In combination with sensitive, label-free targeted MS for phosphorylation site validation, our approach is ideally suited to exploring cellular phosphorylation based signaling networks in high detail.