The molecular target of rapamycin (mTOR), which is a member of the 
phosphoinositide 3-kinase related kinase (PIKK) family and a central modulator 
of cell growth, is a prime strategic target for anti-cancer therapeutic 
development. mTOR plays a critical role in transducing proliferative signals 
mediated through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) 
signaling pathway, principally by activating downstream protein kinases that are 
required for both ribosomal biosynthesis and translation of key mRNAs of 
proteins required for G(1) to S phase traverse. By targeting mTOR, the 
immunsuppressant and antiproliferative agent rapamycin (RAP) inhibits signals 
required for cell cycle progression, cell growth, and proliferation. RAP, a 
complex macrolide and highly potent fungicide, immunosuppressant, and 
anti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP gains 
function by binding to the immunophilin FK506 binding protein 12 (FKBP12) and 
the resultant complex inhibits the activity of mTOR. Since mTOR activates both 
the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation 
factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream 
signaling elements, which results in cell cycle arrest in the G1 arrest. RAP 
also prevents cyclin-dependent kinase (cdk) activation, inhibits retinoblastoma 
protein ((p)Rb) phosphorylation, and accelerates the turnover of cyclin D1 that 
leads to a deficienciy of active cdk4/cyclin D1 complexes, all of which 
potentially contribute to the prominent inhibitory effects of RAP at the G(1)/S 
phase transition. Both RAP and several RAP analogs with more favorable 
pharmaceutical properties have demonstrated prominent growth inhibitory effects 
against a broad range of human cancers in both preclinical and early clinical 
evaluations. This review will summarize the principal mechanisms of action of 
RAP and RAP derivatives and their potential utility of these agents as 
anti-cancer therapeutics. The preliminary results of early clinical evaluations 
with RAP analogs and the unique developmental challenges that lie ahead will 
also be discussed.