Cetaceans are among the most specialized mammals and are completely dependent and adapted to the aquatic environment. The adaptation to this lifestyle has required complex changes of physiological systems, behavior and morphology. The paleontological history of 50 millions of years of evolution are well documented, but less known is the molecular trajectory behind the transition from land to sea. Identifying genes that have been subjected to selection pressure during cetacean evolution would greatly enhance our knowledge of the ways in which genetic variation in this mammalian order has been shaped by natural selection. This talk will present results from a genome-wide scan for positive selection and case-by-case analysis of candidate loci associated with adaptation to a fully aquatic life from a terrestrial life. Regarding the case-by-case analysis, we studied the molecular evolution of globin genes (hemoglobin and myoglogin) given their important role in hypoxic adaptation. Also, given the importance of hair loss in cetacean lineage to aquatic adaptation, we combined the available genomic information with phylogenetic analysis to conduct a comprehensive analysis of the evolutionary patterns of keratin gene clusters. Moreover, we investigated the molecular evolution of Hox genes in cetaceans and other aquatic mammals (pinnipeds and sirenians) once these genes are known to have important roles in establishing identity to the body parts during development. Taken together, the genome-scanning and the candidate genes analyses provide a insight into the type of biological processes that have been targets of selection in cetacean evolution.