Abstract Understanding the mechanisms and identifying regulators of immune cell development and differentiation are critical for developing new and more effective therapeutics. The fast advancement of genomic technologies provides an unprecedented opportunity to study the immune cells at the system level. The noise in the high throughput measurements and the complexity of multiple omics data make it an urgent need for developing novel and powerful systems biology approach for integrative analysis to reveal the underlying regulatory mechanisms for immune system. We propose a new method to integrate multiomics data at the genetic network level for identification of key regulators deciding the cell state and cell fate (Specific Aim 1). We will apply the method to systematically uncover the regulatory mechanisms in the mouse immune system by analyzing 86 immune cell populations (Specific Aim 2). We will also perform comparative analysis of the human and mouse immune cells to reveal the conserved regulatory code for immune cell specification (Specific Aim 3). We will rigorously assess the performance of the computational analysis, experimentally confirm the importance of the identified key regulators and investigate their roles in regulating immune cell functions. Once complete, the proposed work will provide not only a general tool for integrative analysis of multiomics data but also specific mechanistic insights for understanding the regulation of immune system functions.