Plants have traditionally been used as a source of lead compounds in the development of drugs. Plants have also been the source of several drugs, which are currently the mainstay for the treatment of major diseases such as malaria and cancer. This has led to continued research for new drugs, leading to new bioprospecting initiatives for novel lead compounds. However, there are challenges that have been encountered in drug discovery from plants, which have led to many pharmaceutical companies shunning away from this venture. In this chapter, we discuss the factors affecting the choice for plant-based products in drug discovery. The main factors considered include abundance of plant or sources material, efficacy of plant material/compound, ease of structural modification, molecular size, toxicity, and stability of the compounds. Highlights on how and why each of these factors is considered important have been addressed.