Mutations of Nav1.1 (SCN1A) voltage-gated Na+ channel are the most common known cause of genetically determined epilepsy, causing epileptic syndromes that range in severity from relatively mild disorders such as simple febrile seizures (sFS) and generalized epilepsy with febrile seizures plus (GEFS+) to the epileptic encephalopathy termed Dravet syndrome (DS) or severe myoclonic epilepsy of infancy (SMEI). They can cause also familial hemiplegic migraine (FHM), a severe inherited subtype of migraine with aura. The functional effects of Nav1.1 mutations have not been completely clarified yet, impairing the identification of their pathogenic mechanism and the development of targeted therapies. We have studied an animal model of DS, Nav1.1 knock out mice, and Nav1.1 missense mutations engineered in the human clone and expressed in cell lines or cultured neurons. We have shown that in Nav1.1 knock out mice loss of function of Nav1.1 causes reduced excitability of GABAergic interneurons and reduced network inhibition in hippocampal slices. We have also obtained evidences that Nav1.1 epileptogenic missense mutations can cause loss of function of Nav1.1 by inducing folding defects that can be rescued by interacting proteins and drugs. Moreover, our results show that FHM mutations cause gain of function both in cell lines and in neurons. Our data point to a loss of function as the main effect of epileptogenic Nav1.1 mutations, in some cases because of folding defects, and to a gain of function as the effect of FHM mutations.