The goal of this review is to discuss new approaches to avoid CNI/CCS toxicities with a focus on new biologics and new methods to understand transplant rejection at the single-cell level.Recently developed biologics hold significant promise as the next wave of therapeutics designed to promote CNI/CCS-free long-term allograft acceptance. Indeed, belatacept, soluble CTLA4-Ig, is largely devoid of CNI-like toxicities, although it is accompanied by an increased frequency of acute rejection. Besides belatacept, other biologics hold promise as CNI-free immune suppressive approaches. Finally, powerful new single cell approaches can enable characterization of cellular populations that drive rejection within the rejecting allograft.We propose that the incorporated single cell profiling into studies investigating new biologics in transplantation, could be tailored to each patient, correlated with potential biomarkers in the blood and urine, and provide a platform where therapeutic targets can be rationally defined, mechanistically-based, and exploited.