The modern approach to the development of new chemical entities against complex diseases, especially theneglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets.Among the advantages, this approach allows (i) the search and identification of lead compounds with definedmolecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a greatnumber of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of com-pounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts aswell as of pure substances. The current use of such technology, unfortunately, is concentrated in developed coun-tries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innova-tive new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the countryin a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value.The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set ofselective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by theseforces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazil-ian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural com-pounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes somestrategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomicalstudies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecularcloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are themethods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plantextract preparations, fractionation of promising plant extracts, propagation protocols and definition of in plantastudies to maximize product yield of plant species producing active compounds have to be performed to provide acontinuing supply of bioactive materials. Chemical characterization of natural compounds, determination of modeof action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biologicalassays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thoroughknowledge on which to base the search for natural compounds or their derivatives with biological activity.