Molecular processes involved in the development of malignancy have a role to play in the establishment of the multidrug resistant (MDR) phenotype. Analysis of oncogene expression, at the mRNA level using RT-PCR, in resistant variants of the human squamous lung cell line, DLKP, and the human ovarian carcinoma cell line, OAW42, was carried out in this study. Analysis of gene expression, by RT-PCR and in situ hybridisation, on tumours from breast cancer patients was also carried out on fresh and formalin-fixed paraffin-embedded tissue. Altered expression of c-erbB-2, c-Ha-rov, c-myc and c-fos and the bcl-2 family members, bclxL and bax, were seen in resistant variants of the DLKP cell line developed by continuous exposure to adriamycin, carboplatin and VP-16. Ribozyme technology was used to downregulate the expression of the c-fos gene in the adriamycin-selected variant, DLKP-A, and the effect on adriamycin toxicity was analysed. Drug-resistant cell lines developed by continuous exposure to drug for prolonged periods are frequently resistant to drug concentrations above those achieved in the clinic. As patients can develop drug resistance after only a few courses of chemotherapy, a more clinicallly relevant in vitro model of drug resistance was developed in this thesis by pulse exposure of clonal populations of DLKP, DLKP-SQ and DLKP-I, to clinically attainable levels of adriamycin for a short period of time. The resulting resistant variants, DLKP-SQ/A25010p and DLKPI/ A25010p, exhibited a classical MDR phenotype in that increased resistance to adriamycin, vincristine and VP-16 was demonstrated. However, no alteration in 5-fluorouracil sensitivity was seen. The cell lines were found to over-express the mdrJ gene and decreased adriamycin accumulation was observed in the resistant variants. Characterisation of the resistant variant of DLKP-SQ revealed increased expression, using RT-PCR, of the bcl-xL, bax, c-erbB-2 and c-fos genes relative to the sensitive parental line. To counter-act the effect of bcl-xL over-expression in the DLKP-SQ/A25010p, the antagonistic bcl-xs gene was introduced into the resistant cell line, which resulted in increased sensitivity to adriamycin, VP-16 and vincristine but not to 5-fluorouracil. Attempts were made throughout the course of this thesis to determine the initialising events in the establishment of the MDR phenotype in the pulse-selected model. Results found indicate that bcl-xL and c-fos may be important initialising events in this process. Molecular studies of gene expression pattern in the pulse-selected variant of DLKP-SQ suggested that this may be a novel system amenable to the search for inhibitors of resistance development. Initial studies have been carried out in this thesis to determine if known inhibitors/circumventors of the MDR phenotype or oncogene signalling cascades affected the development of resistance using the DLKP-SQ model.