FROM St. Louis (Forest Park) and points south
Take I-64 West to I-170
Take I-170 North to I-70
Take I-70 West to MO-79
Take MO-79 North to Hannibal

FROM St. Louis County (Kirkwood) and points south
Take I-270 North to I-70
Take I-70 West to MO-79
Take MO-79 North to Hannibal

FROM Springfield, Illinois and points north and east

Take I-72 West to US-36
Take US-36 West to Hannibal

FROM Columbia, Kansas City and points south and west

Take I-70 East to US-54
Take US-54 East to US-61
Take US-61 North to Hannibal

     OR Take the Great River Road route
     Take I-70 East to MO-79 near St. Peters
     Take MO-79 North to Clarksville

FROM  Des Moines and points west and north

Take I-80 East to US-63 (near Grinnell, Iowa)
Take US-63 South into Missouri to US-136
Take US-136 East to Wayland to MO-30
Take MO-30 South to US-61
Take US-61 South to Hannibal