As the amount of information available to biologists increases exponentially, data analysis becomes progressively more challenging. Sequence homology has been a traditional tool in the researchers' armamentarium; it is a very versatile instrument and can be employed to assist in numerous tasks, from establishing the function of a gene to determination of the evolutionary development of an organism. Consequently, numerous specialized tools have been established in the public domain (most commonly, the World Wide Web) to help investigators use sequence homology in their research. These homology databases differ both in techniques they use to compare sequences as well as in the size of the unit of analysis, which can be the whole gene, a domain, or a motif. In this paper, we aim to present a systematic review of the inner details of the most commonly used databases as well as to offer guidelines for their use.