Transcript levels are a critical determinant of the proteome and hence cellular function. Because the transcriptome is an outcome of the interactions between genes and their products, it may be accurately represented by a subset of transcript abundances. We developed a method, Tradict (transcriptome predict), capable of learning and using the expression measurements of a small subset of 100 marker genes to predict transcriptome-wide gene abundances and the expression of a comprehensive, but interpretable list of transcriptional programs that represent the major biological processes and pathways of the cell. By analyzing over 23,000 publicly available RNA-Seq datasets, we show that Tradict is robust to noise and accurate. Coupled with targeted RNA sequencing, Tradict may therefore enable simultaneous transcriptome-wide screening and mechanistic investigation at large scales.