Recombinant tissue-plasminogen activator (rtPA) is the only drug used during the acute phase of stroke. Despite its important benefits, a percentage of patients suffer symptomatic hemorrhagic transformations or a lack of early recanalization rates. These undesirable effects are associated with acute neurological and long-term functional deterioration. For the past 20 years, pharmacogenetic studies have tried to find the genetic risk factors associated with rtPA response. Most of these studies have used a gene-candidate strategy; however, recent genome-wide association studies have emerged indicating that genetic predisposition could modulate rtPA response. This review summarizes the most interesting findings in this field, including which genes and genetic variations are associated with hemorrhagic transformations and recanalization rates after thrombolytic therapy.