Recent studies have documented the biochemical and clinical efficacy of novel aromatase inhibitors. These drugs belong to one of two classes: non-steroidal and steroidal drugs, known to be different with respect to enzyme binding site and their effect on the aromatase enzyme. Several studies have now confirmed a lack of complete cross-resistance to drugs of the two classes. While some of these observations may be explained by a more potent aromatase inhibition caused by some aormatase inhibitors compared to others, this is not always the case. Such observations therefore focus on the importance of alternative mechanism of action like a differential influence on the intratumour aromatase enzyme by the different drugs. Current and future studies should aim at exploring the mechanism of cross-resistance and evaluate optimal use of different aromatase inhibitors in sequence or probably, also in concert.