One of the common forms of multidrug resistance (MDR) is caused by activation of the mdr1 (ABCB1) gene, resulting in overexpression of P-glycoprotein (P-gp) and conferring cancer cell resistance to a broad range of chemotherapeutics. Recently, P-gp-mediated MDR has been associated with aberrant expression of microRNAs (miRNAs) in several types of cancer. miRNAs are small noncoding RNAs that regulate gene expression in a posttranscriptional manner through partial or total hybridization with specific sequences in the 3'-UTR of target mRNAs. Interestingly, there are at least two reports that suggest an additional regulation by miRNAs at the mdr1 promoter level. Here, we critically analyzed some of the miRNAs that regulate P-gp expression at two different levels: posttranscriptional and transcriptional. We proposed that the latter may occur through two possible scenarios: (1) direct miRNA hybridization with an active promoter and (2) triplex structure formation (double-stranded DNA/RNA) stabilized by Argonaute 2. Also, we classified transcriptional gene silencing (1) by homology, represented by small interfering RNAs directed to viral promoters, and (2) by complementarity (Watson-Crick/Hoogsteen base pairing), mediated by miRNAs. Transcriptional regulation could represent a new avenue of knowledge applicable to the modulation of other genes mediated by these noncoding RNAs.