The role of inflammation in cardiovascular disease (CVD) is now widely accepted. Immune cells, including T cells, are influenced by inflammatory signals and contribute to the onset and progression of CVD. T cell activation is modulated by T cell co-stimulation and co-inhibition pathways. Immune checkpoint inhibitors (ICIs) targeting T cell inhibition pathways have revolutionized cancer treatment and improved survival in patients with cancer. However, ICIs might induce cardiovascular toxicity via T cell re-invigoration. With the rising use of ICIs for cancer treatment, a timely overview of the role of T cell co-stimulation and inhibition molecules in CVD is desirable. In this Review, the importance of these molecules in the pathogenesis of CVD is highlighted in preclinical studies on models of CVD such as vein graft disease, myocarditis, graft arterial disease, post-ischaemic neovascularization and atherosclerosis. This Review also discusses the therapeutic potential of targeting T cell co-stimulation and inhibition pathways to treat CVD, as well as the possible cardiovascular benefits and adverse events after treatment. Finally, the Review emphasizes that patients with cancer who are treated with ICIs should be monitored for CVD given the reported association between the use of ICIs and the risk of cardiovascular toxicity.