•Genomic signatures of host-adaptation and virulence of Salmonella are emerging.•Sequence analyses can aid the prediction of zoonotic risk and source attribution.•Host-specific, niche-specific and variant-specific virulence factors have been identified.•Comparative and functional genomics identify options for control of Salmonella.•Rodent and cell-based assays do not always reflect salmonellosis in farm animals. Salmonella is an animal and zoonotic pathogen of global importance. Depending on pathogen and host factors, infections can be asymptomatic or involve acute gastroenteritis or invasive disease. Genomic signatures associated with host-range, tissue tropism or differential virulence of Salmonella enterica serovars, and their variants, have emerged. In turn, it is becoming feasible to predict invasive potential, host-adaptation and zoonotic risk of Salmonella from sequence data to improve outbreak investigation, risk assessment and control strategies. Functional annotation of Salmonella genomes has accelerated with the screening of high-density mutant libraries, revealing host-specific, niche-specific and serovar-specific virulence factors. As natural hosts and reservoirs, farmed animals provide powerful insights into host-adaptation and pathogenesis of Salmonella not always evident from surrogate rodent or cell-based models.