The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways to develop targeted treatments, as well as to identify prognostic and predictive biomarkers. Although the majority of efforts have been focused on tyrosine kinase inhibitors (TKIs) and tyrosine kinase receptor (RTK)-targeting antibodies, efforts and interests are also being directed towards serine/threonine kinases and protein phosphatases. Unfortunately, inhibitors often lack specificity and affect various kinases. In addition, treated tumors acquire drug resistance and relapse, requiring second-line treatments. With the advent of precision medicine, it is clear that networks are more robust biomarkers than individual proteins and genes. Drug development is moving to dynamic signaling network targeting. In the postgenomic era, post-translational modifications such as protein phosphorylation and how they affect activity or network architecture remain poorly understood. This Special Issue, dedicated to the unraveling of the protein phosphorylation signaling pathways in cancer, includes seven review articles and six original research papers from over 80 scientists from more than seven countries worldwide.