Abstract The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, all display distinct clinical presentations. The basis of these distinct clinical presentations is the enhanced vulnerability of specific neuronal cell types to death or dysfunction in each disease, despite widespread expression of disease-associated genes. My work uses innovative approaches to address these long-standing questions of enhanced vulnerability, which have remained open questions in the field for decades. I was centrally involved in developing a widely used cell type-specific profiling methodology known as translating ribosome affinity purification (TRAP) that allows cell type-specific RNA profiling. My lab has recently developed a new genetic in vivo screening platform for the CNS, a powerful new approach for brain studies as it allows for systematically testing the causal effect (versus correlation) of each gene in the genome for disease phenotypes, rather than more standard approaches that test a single gene per animal. Additionally, using single cell sequencing approaches, we have also conducted the largest single cell studies of Huntington’s disease patient tissue conducted to date. These studies have collectively revealed the scope of transcriptional dysregulation in Huntington’s disease and Huntington’s disease model tissue, and also have implicated neuronal innate immune activation as a likely key driver of cell type-specific vulnerability in Huntington’s disease. My long-term research goal, starting with Huntington’s disease as a model disorder, is to elucidate the basis of enhanced vulnerability in neurodegenerative disease, not only as a window for discovering valuable insights into the cell biology of disease-relevant neuronal cell types, but also identifying new therapeutic targets.