Although mammography remains the technique of choice for the early detection of breast cancer, new emerging breast imaging techniques such as ultrasound, magnetic resonance and radionuclide scanning have been investigated and included in many diagnostic protocols. This overview discusses the current problems related to radionuclide breast imaging trying to define its role in the management of women with suspicious breast lesions at mammography. A number of tumor-imaging agents have been recently used for the differential diagnosis of malignant and benign lesions in radiographically dense breasts and breasts with architectural distortions from prior biopsy or surgery or following radiation therapy. 99mTc-MIBI is the most used tracer which has become the paradigm of this new class of compounds suitable for breast imaging. The current sensitivity and specificity rates for breast scintigraphy with 99mTc-MIBI depend on a number of factors including lesion size and site. Sensitivity and specificity rates and positive and negative predictive values of 92, 89, 81 and 96%, respectively, have been reported in a large series of patients with palpable breast lesions, which figures have been confirmed in many other series. On the contrary, lower sensitivity has been reported for nonpalpable breast abnormalities or for lesions smaller than 1 cm. This observation, confirmed by many authors, implies that a new nonpalpable lesion that is suspicious for malignancy at mammography needs a histologic diagnosis. We also report the results of our recent studies on functional imaging with 99mTc-MIBI of the multidrug resistance phenotype in breast cancer patients. These studies followed an observation that this tracer is a suitable transport substrate for the P-glycoprotein (P-gp) which is commonly associated with the development of a multidrug resistance phenotype. We examined 30 patients with histologically confirmed breast carcinoma who had received no previous chemotherapy or preoperative local irradiation. We found a positive and significant correlation between the efflux rates of 99mTc-MIBI determined by in vivo kinetic analysis and the P-gp levels measured in vitro by quantitative autoradiography in the same tumors (r = 0.62; p < 0.001). More recently, we tested whether tumor clearance of 99mTc-MIBI can predict the response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Thirty-nine patients with stage III disease underwent 99mTc-MIBI scanning before neoadjuvant chemotherapy and the time to half-clearance of the tracer was calculated. The patients then received epirubicin and underwent mastectomy after completing chemotherapy. This study showed that a rapid tumor clearance of 99mTc-MIBI (< or = 204 min) can predict the lack of tumor response to neoadjuvant chemotherapy with drugs affected by multidrug resistance phenotype in advanced breast carcinoma patients. However, slower tracer clearance (> or = 204 min) did not guarantee an objective tumor response to chemotherapy in all patients, in agreement with the existence of several P-gp-independent mechanisms of drug resistance. We conclude that the preliminary study of this phenotype would allow to predict the response to (neo)adjuvant chemotherapy and select the appropriate treatment regimen for each patient. Finally, radionuclide breast scanning may be helpful in the differential diagnosis of malignant and benign breast lesions as a guide to subsequent chemotherapy.