Abstract: A common feature among neurodegenerative conditions is that certain neuronal populations are selectively vulnerable to loss (Fu et al., 2018). By corollary, other neurons are selectively resilient, suggesting they may possess unique features that support their survival. Understanding the basis of neuronal resilience or vulnerability would provide a logical strategy to identify factors that could be targeted therapeutically. Recent advances in cell-type resolved transcriptomic approaches, in particular single-cell RNA-sequencing (scRNA-seq), are enabling the dissection of neuronal resilience/vulnerability with increasing scale and precision across a variety of neurodegenerative conditions. These transcriptomic approaches can yield new insight into degenerative mechanisms but require thoughtful experimental design and analytical methods to be applied to complex disease models. In this perspective, we highlight recent studies focusing on two characteristically distinct forms of neurodegeneration that employ innovative transcriptomic approaches to similarly determine molecular features associating with resilience and vulnerability. First, we discuss studies on retinal ganglion cell (RGC) degeneration after acute axonal injury, a relatively approachable model which has been particularly fruitful for the discovery of genes that mediate neuroprotection and axon regeneration. Next, we present how similar approaches have been extended to study Alzheimer’s disease (AD), where studying selectively vulnerable populations has been historically challenging. Together, the success of these studies in revealing disease modifiers across degenerative conditions serves as a practical demonstration of the general utility of this research framework. In conclusion, cell-type resolved transcriptomics is a powerful approach to studying selective vulnerability and has the potential to spur the development of improved treatments for neurodegenerative conditions where traditional methods have stalled.