The post-genomics era has provided researchers with access to a new generation of tools for the global characterization and understanding of pathogen diversity. This review provides a critical summary of published Leishmania post-genomic research efforts to date, and discusses the potential impact of the addition of metabolomics to the post-genomic toolbox. Metabolomics aims at understanding biology by comprehensive metabolite profiling. We present an overview of the design and interpretation of metabolomics experiments in the context of Leishmania research. Sample preparation, measurement techniques, and bioinformatics analysis of the generated complex datasets are discussed in detail. To illustrate the concepts and the expected results of metabolomics analyses, we also present an overview of comparative metabolic profiles of drug-sensitive and drug-resistant Leishmania donovani clinical isolates.