Kinases regulate normal physiological response to environmental perturbations. When dysregulated, either through aberrant expression or mutation, protein and lipid kinases have been implicated in a host of diseases, from metabolic disorders to cancer. Tyrosine kinases were among the earliest oncogenes, and have emerged as primary drivers of multiple cancer subtypes. Accordingly, many of the targeted therapeutics for cancer, including small molecule and biological agents, have been generated against oncogenic kinases. Unfortunately, the therapeutic efficacy of these molecularly targeted agents has been largely disappointing due to the emergence of therapeutic resistance, much of which is caused by rewiring of the signaling network. Understanding the normal physiological role of protein kinases, as well as their altered substrates and signaling networks in disease states, will significantly improve our ability to selectively target disease- associated kinases and will enable the development of next-generation targeted combinatorial therapeutics with greatly increased efficacy. Some of the main challenges in the field are to improve our knowledge of how kinases regulate cell states and control cellular plasticity, and how kinase signaling networks respond to cellular stress associated with therapeutic treatment. There are three specific objectives of the FASEB 2014 Protein Kinases, Cellular Plasticity and Signal Rewiring Conference. The first objective is to describe the state of the art in kinase structure, function, localization, regulatin, interactions, and targeting in both normal and pathological cell states, as this information will provide critical clues as to how to differentially affect diseased states and thereby increase the therapeutic window, as defined by the difference between targeting the disease and developing toxic side effects. To accomplish this goal we have planned a series of keynote and plenary speakers from many of the leading experts in the field, multiple short talks selected from the poster abstracts, poster sessions, question and answer sessions, several focused workshops, and informal discussions. Since the challenges in this field are daunting and will require collaborative efforts to solve them, the second goal is to enhance interactions between academia, industry, and clinical science. To this end, we have specifically invited speakers representing each of these topics, and are planning a workshop to discuss signaling rewiring and cellular plasticity in therapeutic resistance mechanisms. The third objective is to invest intellectually and financially in the future by supporting promising young trainees. The goal is to encourage trainees to be successful and stay in the field by providing intellectual support through discussions with senior scientists, poster sessions, opportunities to speak, awards that recognize their achievements, and by providing financial support with competitive travel awards. The expected outcomes are increased collaborations, retention of young scientists in the field, identification of new developmental processes and diseases linked to tyrosine kinase signaling, and exploration of new avenues and approaches for identifying and developing therapeutic targets and strategies to combat cancer, developmental deficiencies, and other diseases.