Fragment-based drug discovery (FBDD) emerged as a disruptive technology and became established during the last two decades. Its rationality and low entry costs make it appealing, and the numerous examples of approved drugs discovered through FBDD validate the approach. However, FBDD still faces numerous challenges. Perhaps the most important one is the transformation of the initial fragment hits into viable leads. Fragment-to-lead (F2L) optimization is resource-intensive and is therefore limited in the possibilities that can be actively pursued. In silico strategies play an important role in F2L, as they can perform a deeper exploration of chemical space, prioritize molecules with high probabilities of being active and generate non-obvious ideas. Here we provide a critical overview of current in silico strategies in F2L optimization and highlight their remarkable impact. While very effective, most solutions are target- or fragment- specific. We propose that fully integrated in silico strategies, capable of automatically and systematically exploring the fast-growing available chemical space can have a significant impact on accelerating the release of fragment originated drugs.