Cancer is a multi-step disease involving dynamic changes in the genome. However, studies on cancer genome so far have focused most heavily on protein-coding genes, and our knowledge on alterations of the functional noncoding sequences in cancer is largely absent. MicroRNAs (miRNAs) are endogenous small noncoding RNAs weighing 20 to 23 nucleotides that negatively regulate gene expression at the posttranscriptional level by base pairing to the 3 untranslated region of target messenger RNAs. Hundreds of miRNAs have been identified in humans and are evolutionarily conserved from plants to animals. These tiny but potent molecules regulate various physiological and pathological pathways such as cell differentiation and cell proliferation. Recently, miRNA alterations have been linked to the initiation and the progression of human cancer. As a consequence, MiRNA-expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target proteincoding genes involved in cancer. Of importance, pioneering studies described let-7 miRNA as a negative regulator of the oncogenic family of Ras guanosine triphosphatases in both Caenorhabditis elegans and human tumor cell lines. Later, let- 7 expression deregulation was reported in several cancers, suggesting that let-7 may act as a tumor suppressor. This review will discuss the late insights in let-7 function, the relationship between let-7 and tumorigenesis, and the potential for modulating let-7 expression for the treatment of cancer.