Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin–angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. This evidence concerns the gene REN and Cluster headache.