The zebrafish (Danio rerio) has been increasingly explored in pharmaceutical research as a promising alternative model for toxicological screens. This necessitates a thorough knowledge on the biotransformation processes for a correct interpretation of pharmacological and toxicological data. Physiologically, cytochrome P450 (CYP) enzymes, specifically CYP families 1-3, play a pivotal role in drug metabolism. And yet, information regarding activity of CYP, its isoforms, and conjugation enzymes in zebrafish is either scarce or conflicting. To account for this discrepancy, the available spatiotemporal, modulation and activity data on zebrafish CYP 1-3 families are reviewed in this paper and compared with human CYP data. The CYP genetic features and synteny are well characterized, as is their expression in different organ systems. Moreover, several substrates metabolized by humans also show metabolism in zebrafish, with other CYP isoforms possibly involved. Altogether, the five CYP1 members, 41 CYP2 members and five CYP3 members in zebrafish show distinct evolutionary and orthological similarities with humans.