Chimeric antigen receptor (CAR) T cells are engineered T lymphocytes that redirect the immune cell against a specific target antigen. As a novel immunotherapeutic method, CAR T cells have shown promising results against malignancies with hematologic sources. By the end of 2021, five CAR T products have been approved by the food and drug association (FDA) for B-cell malignancies. Nevertheless, this immunotherapeutic method has not shown impressive results against solid tissue-derived cancers. Understanding the molecular and cellular mechanisms underlying the road backs of CAR T therapy in solid tumors, such as the physical and metabolic barriers, immunosuppressive immune cells and soluble factors, insufficient immune cell homing to the tumor site, and tumor antigen heterogeneity can pave the way to engineer novel CAR T products with higher specificity. In this chapter, we review the current progress of preclinical and clinical studies of CAR T cell therapy in different solid tumors, including lung, liver, renal, breast, gastric, prostate, ovarian, pancreatic, and colorectal malignancies. Moreover, obstacles that reduce the efficacy of CAR T therapy in solid tumors and solutions to these barriers, by focusing on recent novel CAR structures engineered to improve CAR T cell recognition, specificity, and survival in solid tumors are discussed in detail.