Fish red blood cells contain nucleus and therefore carry on active transcription throughout their life. As the steady state level of mRNA depends both on the production and breakdown of the mRNA, it is important to pay attention to sampling, cell separation, mRNA extraction, and transcript stability to conduct a comprehensive erythrocyte genomics study. In addition, particular attention should be made to tie the transcriptional changes to corresponding protein activities, as only those would impact cellular functions. Here, we thus describe the different steps to conduct comprehensive functional genomics studies with fish erythrocytes.