The current state of the art in CAR-modified T cell therapy in the clinic is focused on CD19-specific second-generation vectors that encode a 4-1BB (CD137) and CD3ζ-chain signaling package (see NCT02030847 and NCT01626495 at clinicaltrials.gov). Interestingly, because of the high activity of anti-CD19 CARs, the CD28 and CD3ζ-chain signaling package is still highly effective against disease and may be entirely suitable, especially if the patient goes on to HSCT (see NCT01593696, NCT00586391, and NCT00924326). The combination of CAR-based therapy with lymphodepletion or immune checkpoint blockade (such as anti-PD-1 or anti-CTLA4 antibody) demonstrates that we are in a rapidly changing clinical study environment in which new insights towards the effective use of CAR-T cells against hematologic malignancies will continue to develop. In scenarios where immune activity is potentiated, a less active CAR (at least as defined in the laboratory) may be more desirable. Given the rapid translation of CAR-T cell therapy into the clinic, where are the next breakthroughs going to come from? First will be with regard to the viral vector technology. Currently lentivirus-based approaches are state of the art. However, this represents a cost and developmental bottleneck; thus, new transfection-based approaches are awaiting development. Second, the ability to define the most effective CAR-T cell populations with regard to phenotype and the ability to direct their developmental state through cytokines or modification of signal transduction pathways (such as with mTOR inhibitors) will continue to refine current culture techniques and approaches. The goal would be the ability to more rapidly define or create T cell populations that could be infused at lower doses (thus requiring less laboratory effort) while retaining high antileukemic activity. Finally, the demonstration of an effective CAR-based therapy against a solid tumor awaits clinical confirmation. The high degree of normal tissue damage that has been seen in some trials indicates that tissue destruction is indeed possible. However, we do not yet know if it is a paucity of truly tumor-specific cell surface targets or if it the tumor microenvironment that prohibits clinical antitumor effectiveness. The recent opening of a trial featuring a third-generation CAR specific for the pediatric tumor-associated antigen GD2 is of interest in this regard. The retroviral vector used in this trial expresses a GD2-specific binding motif and a combination of CD28, CD3ζ, and OX40 signaling motifs (see NCT01822652). This signaling combination is thought to perform similar to the 4-1BB second-generation vectors, where the anti-apoptotic properties of a TNF-receptor superfamily member (OX40, TNFRSF4, or CD137, TNFRSF9) may enhance survival of the transduced cells once they are infused. This vector also encodes an iCaspase-9 safety gene. If this credentialed tumor-specific anti-GD2 scFv fails to make an impact on disease in a CAR setting, this indicates that engineered T cells alone cannot overcome the solid tumor microenvironment and future successes will hinge on altering this milieu. If the GD2-specific CAR is effective, we will have turned an important first corner in treating solid tumors with engineered T cells.