In eukaryotes, proteins containing RNA Recognition Motifs (RRMs) are involved in many different RNA processing reactions, RNA transport, and mRNA decay. Kinetoplastids rely extensively on post-transcriptional mechanisms to control gene expression, so RRM domain proteins are expected to play a prominent role. We here describe the results of an RNA interference screen targeting 37 of the 72 RRM-domain proteins of Trypanosoma brucei. RNAi targeting 8 of the genes caused clear growth inhibition in bloodstream trypanosomes, and milder effects were seen for 9 more genes. The small, single-RRM protein TbRBP3 specifically associated with 10 mRNAs in trypanosome lysates, but RBP3 depletion did not affect the transcriptome.