The global gene expression profiling of early T helper (Th) 1 and Th2 differentiation reveals that this process can be divided into two stages, activation and differentiation. The activation stage is manifested in coordinated mobilization of the replication machinery, a process that we hypothesize may be responsible for establishing genomewide opening of transcription loci. The molecular programs underlying the differentiation stage consist of highly regulated expression of functional groups of genes that are important for the biological properties of Th1/2 cells and transcription factors that are likely important in establishing terminal differentiation of these cells. The kinetics of expression pattern of a number of transcription factors shed new light on the molecular events that shape the outcome of Th1/2 differentiation.