Heteromorphic sex chromosomes induce potentially deleterious gene expression imbalances that are frequently corrected by dosage compensation (DC). Three distinct molecular strategies to achieve DC have been previously described in nematodes, fruit flies and mammals. The reason for these mechanistic differences remain unclear: Are they a consequence of distinct genomes and gene content, functional or ecological constraints, or random initial commitment to an evolutionary trajectory? Here, we study DC in the malaria mosquito Anopheles gambiae. The X chromosomes of Anopheles and Drosophila evolved independently, yet from the same ancestral autosome and share a high degree of homology. We find that Anopheles achieves DC by an entirely different mechanism compared to the MSL complex - H4K16ac axis operating in Drosophila. CRISPR knock-out of msl-2 in Anopheles leads to early embryonic lethality and affects both sexes. Transcriptome analyses indicate that this phenotype is not a consequence of defective X chromosome DC, but instead relates to misregulation of developmental genes. Furthermore, Histone H4 Lysine 16 acetylation does not mark an X chromosome territory, neither does it display a sexually dimorphic genome-wide distribution by ChIP. We conclude that a novel pathway confers X chromosome upregulation in male Anopheles. Our findings highlight the pluralism of how organisms cope with gene-dosage alterations and show that different mechanisms can evolve even in scenarios of highly similar genomic and functional constraints. Overall design: RNA-seq in msl-2 KO Drosophila melanogaster and Anopheles gambiae.