In recent years, the discovery of new and effective antibiotics has slowed dramatically due to the rapid and widespread development of bacterial drug resistance and many pharmaceutical companies exiting the field. Reliance on conventional drug discovery methods, while effective in the past, has led to significant present-day challenges that are becoming increasingly difficult to overcome. A fundamental challenge to the development of new antibiotics against multi-drug resistant bacteria is the high cost of development relative to expected revenues. Fragment-based drug design (FBDD), which involves screening low molecular weight ligands, can help to drastically reduce the cost of finding initial hits compared with traditional highthroughput screening (HTS). In addition, a knowledge-driven and multi-pronged approach to the subsequent expansion of amenable fragments into high-affinity inhibitors may assist with overcoming hurdles in the hit-to-lead (H2L) optimisation process. Favourable pharmacological and physicochemical properties, as well as strategies against the development of resistance, can be incorporated as part of the fragment expansion process. This chapter discusses the features of the FBDD approach that are relevant and beneficial for antibiotic development. Successful examples and barriers to progress from hit discovery to H2L development, as well as patents, are presented. Finally, the outlook for FBDD in the field of antibiotic development, including the latest FBDD advances and challenges, is discussed.