After the successful completion of the human genome project, mapping of the human proteome has become the next important challenge facing the biotech and pharmaceutical industries. Identification of the 'right' target(s) is now a critical part of the process because of the cost of drug discovery. Compounding this situation is the fact that the pharmaceutical industry faces a further challenge of being able to sustain current and historical growth rates. Hence, the discovery of new drug targets is important for developing new drug leads that can become preclinical drug candidates. Proteomics is the next phase of the effort whereby the human genome can be understood. However, mapping the human proteome presents a daunting challenge. Proteomics involves several essential components with the most significant being the discovery and description of all protein-protein interactions. Once this compendium is available, a secondary and equally important initiative will be to decipher proteins that are differentially expressed in any given disease condition. At this point, the critical focus will be to select the most relevant proteins, understand their partner interactions and then further winnow them to the point where they are relevant pharmaceutical target candidates. This paradigm can be compared to finding the relevant 'needle in the proteome haystack'. This review describes the use of genomic and protein-protein interaction technologies to identify and validate these 'needles' as the first step in the drug discovery process.