Despite the maturation of organic chemistry and the efforts of medicinal and combinatorial chemistry, natural products play a preeminent role in drug discovery. However, there is a general lack of information concerning cellular targets of most natural products but, without an understanding of how biologically active natural products work, efforts to generate more potent analogs through structure–activity relationships, structure-based design, or combinatorial chemistry is made more difficult. Similarly important, but even less well known, are the identities of ‘off-targets’ that are responsible for toxicity or side effects of natural product drugs. Chemical proteomics approaches, especially affinity chromatography, dominate the methods used to identify natural product-binding proteins. However, reverse chemical proteomics methods such as phage, mRNA, and ribosome displays have begun to emerge and others such as cell display, protein and chemical arrays, yeast three-hybrid, the viral and DNA displays are methods that hold the promise of being able to rapidly identify natural product-binding proteins. In this chapter, we review various methods that have been used to determine the binding proteins for natural products but also look critically at methods that might be used in the near future to achieve this goal. Each has advantages and disadvantages and there is no one perfect method, but many are complementary. This is certainly a rapidly evolving and exciting facet of natural products research.