The tetraploid and highly heterozygous potato serves as a staple food for billions of people worldwide. Genetic features of the potato make classical breeding strategies challenging because elite cultivars are vegetatively propagated to avoid the loss of optimal agronomic traits through allele segregation during sexual reproduction. Therefore, genome editing is a promising tool for both functional genomics and crop breeding through the efficient introduction of favorable alleles. In the past few years, the plant science community has successfully and extensively applied the powerful, precise, and versatile clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to modify genes of interest and confer new traits in crops, including potato. Until recently, CRISPR was most commonly used to generate knockout mutants, but new CRISPR technologies have emerged that can induce precise modifications in genomic loci of interest. In this chapter, we summarize the current knowledge of genome editing with a special focus on applications in potato. We describe the current CRISPR toolbox that can be applied to potato research and cultivar development, allowing the introduction of a large range of edits in almost any locus of interest. The current advances and challenges specific to potato molecular breeding are also discussed, including strategies to generate transgene-free edited plants. Finally, we review the traits that have been targeted so far and those of interest for future improvement, including pathogen resistance traits that could help meet current environmental challenges, according to international regulatory frameworks.