AbstractGenome instability and aberrant alterations of transcriptional programs both play important roles in cancer. However, their relationship and relative contribution to tumor evolution and therapy resistance are not well-understood. Single-cell RNA sequencing (scRNA-seq) has the potential to investigate both genetic and non-genetic sources of tumor heterogeneity in a single assay. Here we present a computational method, Numbat, that integrates haplotype information obtained from population-based phasing with allele and expression signals to enhance detection of CNVs from scRNA-seq data. To resolve tumor clonal architecture, Numbat exploits the evolutionary relationships between subclones to iteratively infer the single-cell copy number profiles and tumor clonal phylogeny. Analyzing 21 tumor samples composed of multiple myeloma, breast, and thyroid cancers, we show that Numbat can accurately reconstruct the tumor copy number profile and precisely identify malignant cells in the tumor microenvironment. We uncover additional subclonal complexity contributed by allele-specific alterations, and identify genetic subpopulations with transcriptional signatures relevant to tumor progression and therapy resistance. We hope that the increased power to characterize genomic aberrations and tumor subclonal phylogenies provided by Numbat will help delineate contributions of genetic and non-genetic mechanisms in cancer.