Reconstructing the Tree of Life remains a central goal in biology. Early methodologies, relying on comparative anatomy or alignments of small numbers of genetic loci, often yielded conflicting evolutionary histories, undermining confidence in the results. Investigations based on phylogenomics, which uses hundreds to thousands of loci for phylogenetic inquiry, often provide a clearer picture of life's history, but certain branches have remained challenging to resolve. Particularly problematic nodes include the root of the animal tree and the relationships among major clades of teleost fish, a group encompassing nearly half of all vertebrates. To address these debates, recent studies tested the utility of an emerging phylogenomic marker: synteny, the conserved collinearity of orthologous loci in two or more organisms. Synteny exhibits compelling phylogenomic potential, while also raising new challenges. We discuss the history of phylogenetics, contentious branches in the Tree of Life, and the use of synteny to address them. We propose five research questions to help guide the use of synteny data in phylogenomic studies. Synteny-based analyses of highly contiguous genome assemblies mark a new chapter in the phylogenomic era and the quest to reconstruct the Tree of Life.