Chimeric antigen receptor-modified T cell therapy (CAR-T) is known to exhibit distinctive precision, extensiveness, and persistence in anti-tumor immunity, giving rise to its breakthrough and unprecedented success in hematologic malignancy treatment. On the contrary, this therapy is faced with the inherent obstacles of solid tumors, in which the application of CAR-T is restricted. Smooth infiltration into the tumor microenvironment (TME) is the first critical step. Then, tumor-infiltrating CAR-T cells are forced to overcome the inhibitory effects of miscellaneous factors in the TME and achieve the targeted recognition and killing of tumor cells. Any of these steps, if impeded, can seriously threaten both the efficiency and security of CAR-T therapy. Inspiringly, these challenges have failed to hold back the progress being made by studies focusing on the application of CAR-T in solid tumors. In addition, a growing number of promising coping strategies have gradually emerged. Both the problems and solutions associated with the development and application of these therapeutic strategies are summarized in this review.