Abstract: Thermoresponsive polymers with a LCST in aqueous solutions have been extensively studied from the origin of their themo-sensitivity to the modulation of their responsive behaviors. Polymers with a UCST in water, however, are not as common and the design and preparation of such polymers remain a challenge. We proposed a thermodynamic map to guide the rational design of thermoresponsive polymers. The map is a Cartesian coordinate system with the mixing entropy and the mixing enthalpy as the two axes, and is divided into four regions: UCST, LCST, soluble and insoluble as laid out by the free energy change upon mixing. By locating a certain polymer in the map and by plotting its trajectory upon a chemical modification or a physical stimulus, one may predict the responsiveness of a new target polymer and estimate its responsive temperature. The understanding of the enthalpic and entropic contributions in the polymers can help in the rational design of thermoresponsive polymers and will help to enlarge the repertoire of these polymers. Using this map, we have designed and synthesized new polymers possessing a UCST in water from monomers of which the corresponding homopolymers are normally not expected to exhibit thermoreponsive behaviors in water. Such copolymers may be prepared by the tuning of hydrogen-bonding and hydrophobic interactions between the comonomers. The UCST behaviors of such polymers may be varied by copolymerization, host-guest complexation and even light irradiation after the inclusion of photo-responsive functional groups. The preparation of polymers with UCST in aqueous solutions which can respond to multiple stimuli may lead to new designs of functional smart materials.