Force production by myosin motors plays major roles in muscle contraction, intra-cellular trafficking and maintenance of critical cellular structures such as microvilli, stereocilia and invadopodia. Deficit in different myosin motors can lead to a number of serious disease, thus myosins are important potential targets for therapeutical treatment. Structures of myosins in complexes with small molecules reveal unsuspected allosteric sites and provide valuable insights for the design of specific modulators. These reveal the mechanistic control of motor transitions by inhibitors and activators and provide novel understanding of the rearrangements controlling the force producing lever arm swing. Current progress and outstanding questions regarding the important sequential rearrangements that lead to force production by myosins will be presented in light of recently solved X-ray structures of myosin/drug complexes. New insights into the mechanism of allosteric tuning of myosin force generation is thus anticipated to lead the way in the development of new myosin-directed therapeutics.