CAR-T cell therapy has shown promising results in treating malignant hematologic diseases. The principle of this therapy is based on the use of genetically modified T lymphocytes to express a Chimeric Antigen Receptor (CAR) on their membrane that specifically recognizes an antigen predominantly expressed on target cells. The molecular design of the CAR, along with advancements in molecular techniques and the development of "omics", has opened the possibility of discovering new therapeutic targets and thereby expanding the range of diseases treated with CAR-T cells beyond the use of anti-CD19 and anti-BCMA for hematologic cancer. This review summarizes the novel therapeutic targets that are currently used in clinical trials with CAR-T cell therapy on autoimmune diseases and other challenging conditions, such as cardiac fibrosis, and different infections. Additionally, challenges and novel opportunities are discussed for expanding clinical access to this innovative therapy.