The identification of B-cell epitopes in antigens is a crucial step in developing recombinant vaccines or immunotherapies for various diseases. Over the past four decades, numerous in silico methods have been developed for predicting B-cell epitopes. However, existing reviews have only covered specific aspects, such as the progress in predicting conformational or linear B-cell epitopes. Therefore, in this paper, we have undertaken a systematic approach to provide a comprehensive review covering all aspects associated with the identification of B-cell epitopes. Firstly, we have covered the experimental techniques developed over the years for identifying linear and conformational epitopes, including the limitations and challenges associated with these techniques. Secondly, we have briefly described the historical perspectives and resources that maintain experimentally validated information on B-cell epitopes. Thirdly, we have extensively reviewed the computational methods developed for predicting conformational B-cell epitopes from the structure of the antigen, as well as the methods for predicting conformational epitopes from the sequence. Fourthly, we have systematically reviewed the in silico methods developed in the last four decades for predicting linear or continuous B-cell epitopes. Finally, we have discussed the overall challenge of identifying continuous or conformational B-cell epitopes. In this review, we only listed major computational resources; a complete list with the URL is available from the BCinfo website (https://webs.iiitd.edu.in/raghava/bcinfo/ ). This article is protected by copyright. All rights reserved.