Combinatorial gene control is the synergistic action of several transcriptional factors to regulate the expression of a single gene. The absence of one or more of these factors may lead to a significant difference in the level of gene expression or repression.

The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene expression occurs through these proteins working with each other in various combinations to regulate the expression of different genes.

Combinatorial gene control occurs through several different mechanisms. In yeast, three different mechanisms have been described. In the waiting-activating system, all of the transcription factors required to regulate the expression of a gene bind to the DNA and only activate transcription when they receive a signal. For example, transcription factors that regulate genes needed in the late G1 phase of the cell cycle bind to the regulatory site of their target genes in early G1. However, they induce transcription only when a cyclin-protein kinase is activated in the late G1 phase.

In joint-phase combinatorial control, the transcription factors required primarily for a particular phase of the cell cycle remain attached to the regulatory sequence throughout the cell cycle and participate cooperatively in the regulation of genes during other phases. For example, SBF and Fkh2 are two transcription factors that are primarily involved in the regulation of genes that need to be expressed in G1 and G2 phases respectively. However, certain essential genes that need to be expressed in S-phase are also regulated by the combined action of SBF and Fkh2.

The joint-process combination involves the use of a single transcription factor aided by different combinations of other transcription factors for the regulation of different cellular processes. For example, transcription factors that regulate the expression of genes needed in the G1 phase of the cell cycle, also participate in the regulation of genes required for the mating process in association with a different set of regulators.