Over the last twenty years, fragment-based drug discovery (FBDD) has emerged as a highly successful way to provide lead compounds for subsequent optimisation into drug candidates. Initial hits usually exhibit lower potency than those identified by more traditional techniques, such as High-Throughput Screening (HTS), but the optimisation phase of FBDD is highly efficient, thus providing superior lead-like compounds. The recent application of FBDD in a variety of protein kinase campaigns has successfully led to the identification of novel binding sites and highly efficient chemical ligands. This demonstrates the utility of the FBDD strategy against well-established kinase targets, where selectivity is otherwise challenging due to significant conservation of the ATP-binding site. Protein kinase CK2 is a ubiquitously expressed and constitutively active regulator of cell growth, proliferation and apoptosis. Elevated levels of CK2 protein and activity have historically been involved in human cancer, including lung, cervical and head and neck cancer types, and its overexpression is associated with worse prognosis. A number of CK2 inhibitors are currently available displaying activity against multiple cancers in vitro and in the clinic, however the majority of these candidates target the ATP-binding site and thus display poor selectivity in kinase panel assays. Here we explore the application of FBDD towards the development of potent and selective inhibitors of the catalytic α-subunit of CK2. This project exploits a novel, conserved binding site, named the αD pocket, for the generation of allosteric inhibitor molecules. Following structure-based optimisation of a potent inhibitor series, and characterisation of a previously unreported binding mode, a fragment linking strategy between the lead αD-site fragment and a low-affinity pseudosubstrate peptide is investigated. This work validates the utility of FBDD towards the discovery of new binding modes, presents a first in class CK2α allosteric inhibitor series and provides the first X-ray crystal structure of protein kinase CK2 in complex with a ligand binding in the substrate-binding channel.