miR-21 and let-7 are two of the most studied microRNAs (miRNAs), as the former is the most frequently upregulated and the latter is the most frequently down-regulated in cancer. In this short essay, we examine the convergence of miR-21 and let-7 in two major cancer pathways: Ras and NF-κB. miR-21 suppresses multiple targets to enhance the oncogenic action of Ras, while let-7 is a direct negative regulator of the Ras gene family. let-7 is proposed to repress the activation of NF-κB through down-regulation of Ras and IL-6, while miR-21 is demonstrated to enhance NF-κB activation by down-regulating Pten and thereby increasing the activity of Akt, a kinase known to promote the NF-κB pathway. Therefore, miR-21 and let-7 contravene each other in cancer and simultaneous targeting of both is an attractive therapeutic strategy against cancers exhibiting both Ras mutations and constitutive NF-κB activation.