Wilms tumor, the most common kidney cancer in pediatrics, arises from embryonic renal progenitors. Although many patients are cured with multimodal therapy, outcomes remain poor for those with high-risk features. Recent sequencing efforts have provided few biological or clinically actionable insights. Here, we performed DNA and RNA sequencing on 94 Wilms tumors to understand how Wilms tumor mutations transform the transcriptome to arrest differentiation and drive proliferation. We show that most Wilms tumor mutations fall into four classes, each with unique transcriptional signatures: microRNA processing, MYCN activation, chromatin remodeling, and kidney development. In particular, the microRNA processing enzyme DROSHA is one of the most commonly mutated genes in Wilms tumor. We show that DROSHA mutations impair pri-microRNA cleavage, de-repress microRNA target genes, halt differentiation, and overexpress cyclin D2 (CCND2). Several mutational classes converge to drive CCND2 overexpression, which could render them susceptible to cell-cycle inhibitors.