SIRT1 is a highly conserved NAD+-dependent protein deacetylase that is involved in diverse cellular processes. SIRT1 can deacetylate not only histones, but also a growing number of nonhistone substrates involved in multiple signaling pathways. Accumulating evidence has indicated that SIRT1 is a key regulator of life span extension, DNA damage, metabolism stress, inflammation, and cancer. In inflammation, SIRT1 deacetylates several transcription factors and regulates the immune cell responses. In cancer, recent discoveries revealed opposite effects of SIRT1 as an oncoprotein or a tumor suppressor under different conditions. In the tumor microenvironment, both infiltrated immune cells and cancer cells can be affected by SIRT1. Understanding the proper cancer-related functions of SIRT1 in both systems may provide potential evidence for SIRT1-based therapies. Here, we discuss the current understanding of SIRT1 in regulating immune responses and tumorigenesis.