The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. Due to their specific function in mitosis, targeting these proteins creates an opportunity for the development of more selective antimitotics with an improved side effect profile. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs. Drug discovery efforts in this area have initially focused on the plus-end directed kinesin spindle protein (KSP) and a variety of compounds are currently undergoing clinical testing.