Recently, fragment-based drug design has been established as a crucial strategy for hit identification and lead generation, which has strongly encouraged the development of approaches to specifically recognize and evaluate molecular fragments or structural scaffolds that preferentially interact with particular sites of important biological targets. In this context, fragment-based quantitative structure-activity relationship (FB-QSAR) has emerged as a versatile tool to explore the chemical and biological space of data sets of compounds. FB-QSAR approaches have evolved from a classical use in the generation of standard QSAR models into advanced drug design tools for database mining, pharmacokinetic property prediction and optimization of multiple parameters. This paper provides a brief perspective on the evolution and current status of FB-QSAR, highlighting new opportunities in drug design.