Despite notable success over years in the discovery and development of new antiepileptic drugs (AEDs), about 30-40% of the patients are resistant to drug treatment. There is a still significant need to develop novel AEDs that demonstrate superior efficacy, broad spectrum of activities and good safety profile. The synaptic vesicle glycoprotein 2A (SV2A), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) and voltage-gated potassium channels (KCNQ2/Q3) are clinically validated as new molecular targets for epilepsy. The discovery of SV2A as a target for levetiracetam, 2,3-benzodiazepine GYKI 52466 as a non-competitive AMPA-R antagonist and retigabine as a KCNQ2/Q3 channels activator provided a rational basis to develop novel AEDs. The optimization of SV2A binding affinity of levetiracetam led to the discovery of novel high affinity SV2A ligands that displayed superior efficacy and protective index in animal models of epilepsy. The high-throughput screening (HTS) and medicinal chemistry efforts yielded many non-competitive AMPA-R antagonists of which perampanel was recently approved as a first-in-a new class. The efficacy and lack of sub-type selectivity of retigabine prompted many research efforts to discover several potent and selective KCNQ2/Q3 channel activators of distinct chemical scaffolds that are at various stages of clinical development. Despite the known role of galanin and galanin receptor (Gal-R) in epilepsy over a decade, development of potent and brainpenetrant Gal-R agonists is very challenging. The discovery of selective Gal-R2 positive allosteric modulator, CYM 2503, offers a valuable and an alternative approach. The review focuses on the available structure-activity relationships and preclinical efficacy of novel antiepileptic compounds that are distinct from most of the approved AEDs, specifically SV2A ligands, non-competitive AMPA-R antagonists, KCNQ2/Q3 channels activators and Gal-R modulators.