Unmodified deoxyoligonucleotides are rapidly degraded in serum-containing medium. Utilizing internally labelled deoxyoligonucleotides the deoxyribonuclease profile for fetal calf serum and human serum was determined. It was found that the predominate nuclease activity in both systems was 3' exonuclease. Deoxyoilgonucleotides are protected from exonuclease degradation In sera and cell media by simple terminal modifications that maintain high binding affinity for the complementary DNA sequence.