Malaria control interventions have been effective in reducing malaria incidence and mortality rates globally over the last decade. However, increasing resistance of Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax), the two most prevalent parasite species, to the most used antimalarial drugs, threatens to halt the progress. Given the current limited arsenal of antimalarial drugs has been inspired by natural product scaffolds, these have the potential to be the source of new and structurally different antimalarial drugs, acting through novel mechanisms of action, that are urgently needed. Translating the structural and biologically relevant diversity of natural products into an efficient and effective drug development process is, nonetheless, not trivial. Fragment-based drug discovery (FBDD) is a relatively recent and promising approach for drug discovery. It involves the identification of small molecular weight compounds, called fragments, that weakly bind to a biological target and their elaboration through chemical synthesis to produce high affinity and selective drugs. For a rational and effective elaboration process, structural and thermodynamic information are essential.