Immune checkpoints (ICPs) are critical regulators of the immune system and are essential for self-tolerance and the prevention of chronic autoimmune inflammation. Soluble immune checkpoints (sICPs) are shed or secreted by multiple cell types including immune cells, antigen-presenting cells (APCs), and tumor cells, and can impact the efficacy of cancer therapies including immune checkpoint blockade (ICB) via beneficial or detrimental immune modulation. Soluble immune checkpoints are commonly produced by ectodomain shedding of the protein from the cell membrane or by production via alternative splice variants characterized by deletion of the transmembrane domain exon. These soluble checkpoints are often measurable in the circulation of patients with cancer, suggesting the potential roles of sICPs as both biomarkers and therapeutic targets. Like their membrane-bound counterparts, soluble immune checkpoints can be broadly categorized into two groups with opposing functions: stimulatory molecules such as OX40/OX40L, and inhibitory molecules such as PD-1/PD-L1/PD-L2. This chapter aims to examine the contribution of sICPs to the efficacy of immunotherapies, particularly ICB, and to analyze their predictive value in cancer diagnosis and prognosis.