Route 221 is a proposed four-lane road running from Farmington in Saint Francois County to Pilot Knob in Iron County. The route is currently being studied in the Missouri State Transportation Improvement Plan for 2007-2011.

The new route will travel from Farmington to Pilot Knob along Routes V and W. The upgraded road will serve Ironton and Iron County to Saint Francois County (and ultimately, De Soto).

Route W will be totally renamed between Farmington and Pilot Knob, including the Route 221 section. The parts that are not Route 221 will become Routes N and NN around Iron Mountain Lake. The only part that will remain is a small section between Route 221 and Route 32 in Farmington.

Because the current route is a 2-lane road with no shoulder, and many commuters use this route daily (up to 30% of Iron County commuters), it often gets congested and the pavement is not in good condition. The bridge over US 67 will be replaced.