The majority of approved MR contrast agents belong to the class of paramagnetic chelates. These small molecules are uniquely suited to respond to changes in the microenvironment in vivo. These contrast agents can also function as substrates for several classes of enzymes. In both cases, the chelates can be designed in a way that the relaxivity - i.e., the ability of chelated paramagnetic metal cations to shorten the relaxation times of water - is directly affected by changes in the microenvironment. This chapter summarizes a variety of MR contrast agent designs that enable "sensing" of metal cations, pH and enzymatic activity.