Abstract: Bioinformatics and computational biology are major beneficiaries of the current innovations in artificial intelligence and machine learning. While Bioinformatics applies principles of computer science and technique to help understand the vast, diverse, and complex life sciences data and thus make it more useful, in contrast, Computational Biology applies computational approaches to address theoretical and experimental questions in biology. This Special Issue on Computational Intelligence and Machine Learning in Bioinformatics and Computational Biology comprises of extended versions of the key papers from the 18th IEEE Conference on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB, 2021) which is a major event in the field of computational intelligence and its applications to problems in bioinformatics, computational biology, and biomedical engineering. The conference, run annually, provides a global forum for academic and industrial scientists from computer science, biology, chemistry, medicine, mathematics, statistics, and engineering, to discuss and present their latest research findings from theory to applications.