Immune cells are capable of sensing various signals in the microenvironment and turning on specific immune functions in response. The appropriate transition of immune cells into diverse functional states, which is crucial for immunity, involves complex and well-regulated changes in transcriptional program. Accumulating evidence shows that epigenetic remodeling plays a central role in mediating the transcriptional program for immune cell activation and immunological memory. Concurrently, immune cells undergo significant metabolic reprogramming during immune response. Here we review recent studies that demonstrate shifts in metabolic state can orchestrate immune cell functions through its impact on epigenetic remodeling, and the microenvironment can exert its influence on immune cells through the metabolic regulation of epigenetics. We also discuss the systems biology approaches that enabled these discoveries.