Intrinsic or acquired multidrug resistance is the major cause of treatment failure in many human cancers. Multiple cellular mechanisms may contribute to the development of multidrug resistance including overexpression of P-glycoprotein (Pgp). The use of 99mTc-labeled lipophilic cations, which are transport substrate of Pgp, raised the possibility to predict the tumor response to treatment and to identify patients who will become refractory to subsequent therapy. Among these agents, 99mTc-MIBI is the most widely evaluated tracer and may serve as a paradigm of this class of compounds. In particular, many studies have shown the prognostic value of 99mTc-MIBI scan in different types of malignancy including breast cancer and the correlation with the expression of Pgp. However, additional mechanisms of cell resistance, mainly involving alterations of apoptosis, may also affect 99mTc-MIBI uptake in tumors. In particular, overexpression of the anti-apoptotic protein Bcl-2 prevents tumor cells to enter apoptosis and inhibits tracer accumulation into mitochondria. Therefore, while an absent or reduced early tracer uptake in large breast carcinomas reflects the existence of a defective apoptotic program, an enhanced tracer clearance in 99mTc-MIBI positive lesions reflects the activity of drug transporters such as Pgp. The existence of two different mechanisms underlying the predictive role of 99mTc-MIBI scan may be important to establish whether individual patients may benefit from Pgp inhibitors or Bcl-2 antagonists.