MicroRNAs regulate gene expression as part of the RNA-induced silencing complex, where the sequence identity of the miRNA provides the specificity to the target messenger RNA, and the result is target repression. The mode of repression can be through target cleavage, RNA destabilization and/or decreased translational efficiency. Here, we provide a comprehensive global analysis of the evolutionarily distant (from higher plants) unicellular green alga Chlamydomonas reinhardtii to quantify the effects of miRNA on protein synthesis and RNA abundance. We show that, similar to metazoan systems, miRNAs in Chlamydomonas regulate gene-expression primarily by destabilizing mRNAs. However, unlike metazoan miRNA where target site utilization localizes mainly to 3'UTRs, in Chlamydomonas utilized target sites lie predominantly within coding regions. These results demonstrate that destabilization of mRNA is the main evolutionarily conserved mode of action for miRNAs, but details of the mechanism diverge between plant and metazoan kingdoms.