Laurel and Bess Dillard are charismatic bluegrass musicians enjoying the success of their first Southwestern tour. But the Dillard girls know that magical adventures are always at hand. Upon meeting two mysterious strangers at a gig, the red-headed twins are drawn into an age-old, mystical wager along the Medicine Road.

One day, seeing a red dog chasing a jackalope, Coyote Woman gave them both human forms. They became Jim Changing Dog and Alice Corn Hair. In return, both Jim and Alice must find true love within a hundred years, or their ?five-fingered" forms will be forfeit. Alice has found her soul mate, but trickster Jim is unwilling to settle down?until he sets eyes upon free-spirited Bess Dillard.

Yet time is running out for the red dog and the jackalope. In just two weeks, they will journey to their reckoning at the Medicine Wheel. Meanwhile, a motorcycle-riding seductress and a vengeful rattlesnake woman are eager to meddle, and Bess and Laurel, caught in a web of love and lies, must find their own paths into the spirit world.