Introduction The genetics of the primary headaches scored recent scientific successes due to the unravelling of the genetics of FHM. Deciphering of the patho-physiological mechanisms of these common diseases promises to bring the much needed knowledge for pharmacological treatments and therapeutic interventions. There are however also problems and controversies, some not solved by the genetic studies performed to date. The following is a brief subjective review of the available evidence, suggesting a role for epigenetic mechanisms and ending with the proposal of a behavioural model of the primary headaches possibly useful for the genetic studies. Primary and secondary headaches: symptoms, syndromes or diseases? Idiopathic and syndromic migraines symptoms syndromes 1 diseases 1 2 Genetic epidemiology of the typical migraines 3 3 4 5 6 7 8 3 9 10 11 13 Mendelian migraines? The genetics of FHM and their putative relationship with the typical migraines MA/MO CACNL1A4 CACNA1A 14 15 16 CACNA1A 17 CACNA1A CACNA1A 18 19 20 21 22 23 24 CACNA1A 25 26 CACNA1A 27 28 29 30 ATP1A2 31 32 33 34 35 36 37 38 39 40 42 43 ATP1A2 42 SCN1A 44 45 27 2 46 47 48 49 51 CACNA1A 52 55 CACNA1A ATP1A2 ATP1A2 56 57 ATP1A2 58 61 SCN1A 62 CACNA1A ATP1A2 SCN1A 1 Table 1 A list of proposed (and provisional) syndromic migraines Syndromic migraines Genes (chromosome) involved Migrainous features (references) MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) MTTL1  MTTQ  MTTH  MTTK  MTTS1  MTND1  MTND5  MTND6  MTTS2 63 64 CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy) NOTCH 65 66 HERNS (retinopathy, vascular, with cerebral and renal involvement and Raynaud and migraine phenomena) TREX1 67 CCM (familial cerebral cavernous malformations) KRYT 1 68 69 Linkage and association studies in the typical migraines 70 71 72 73 74 75 76 INSR 77 INSR 78 79 80 81 82 84 2 3 4 5 Table 2 Prothrombotic and cardiovascular risk genes and typical migraine genetics Prothrombotic/vascular risk genes or mutations examined Phenotypes LDL receptor (19p13.2) 87 88 Factor V R/Q 506 (Leiden mutation) 89  90 91 92 G/A 91  93 Leu 94 Decanucleotide insertion/deletion factor VII promoter 91 Alloantigenic platelet systems HPA-1 and HPA-2 91 Deficit of protein S 89  (ACE) 95  (NOS3; iNOS) 96 97 (ETA-231 A/G) 98 MTHFR C677T/A1298C 99 100 101 Table 3 Serotonin metabolism genes and typical migraine genetics Serotonin metabolism genes examined  Phenotypes 5-HTSERT 102 103 104 105 106 107 5-HT2A 108 105 106 109 110 5-HT1B 106 110 111 5-HT1D 106 110 111 5-HT2B 106 110 111 5-HT2C 106 110 111 5-HT1B 112 113 5-HT1F 112 113 Table 4 Dopamine metabolism genes and typical migraine genetics Genes examined Phenotypes DRD2 Allelic association (allele NcoI) with MA comorbid with anxiety/depression [114] Allelic association (allele 1) with yawning/nausea during attack of MO [115] 116 107 117 118 119 DRD1, DRD3, DRD4, DRD5 115 117 120 DAT 86 COMT; MAO-A  117 121 (DBH) 107 122 123 Table 5 Other genes implicated in typical migraine genetics Genes examined Phenotypes Androgen/progesterone receptors 124 KCNN3 125  126 (CTLA-4)  127 HLA-DRB1 128 85 86 DRD4 SLC6A3 Genetics of tension-type headache 85 Genetics of cluster headache 129 137 138 141 142 143 144 137 145 148 149 151 CACNA1A 152 153 NOS1 NOS2A NOS3 154 155 CLOCK 156 157 158 HCRTR2 159 160 161 162 163 Genetics and epigenetics Epigenetics is the study of the changes in DNA and DNA-binding proteins that, albeit altering the structure of chromatin, do not modify the nucleotide sequence of DNA. The remarkable feature here is that some of these modifications may be associated with heritable changes in gene function. Commonly held concepts of heredity indeed pit environmental influences (nurture) against genetic background (nature) as totally separate causative factors. Genetic advances themselves have however demonstrated that the hereditary transmission of biological changes not encoded in the DNA sequence and dictated by environmental influences is possible. This part of genetics, called epigenetics, has received little or no attention in the genetic studies of the primary headaches. It is the contention of the author however that future epigenetic studies will account for several hereditary features of the primary headaches, in particular their comorbidities. ATRX FMR1 164 165 Epigenetic models for the primary headaches? 166 167 168 169 170 171 172 173 174 175 176 177 179 180 181 182 Final comments: a behavioural model of the primary headaches as fight-or-flight response and sickness behaviour to be incorporated into genetic research 183 184 185 sickness behaviour 186 187 fight-or-flight response 188 185