Hyperpolarized (129)Xe chemical exchange saturation transfer ((129)Xe Hyper-CEST) NMR is a powerful technique for the ultrasensitive, indirect detection of Xe host molecules (e.g., cryptophane-A). Irradiation at the appropriate Xe-cryptophane resonant radio frequency results in relaxation of the bound hyperpolarized (129)Xe and rapid accumulation of depolarized (129)Xe in bulk solution. The cryptophane effectively "catalyzes" this process by providing a unique molecular environment for spin depolarization to occur, while allowing xenon exchange with the bulk solution during the hyperpolarized lifetime (T(1) ≈ 1 min). Following this scheme, a triacetic acid cryptophane-A derivative (TAAC) was indirectly detected at 1.4 picomolar concentration at 320 K in aqueous solution, which is the record for a single-unit xenon host. To investigate this sensitivity enhancement, the xenon binding kinetics of TAAC in water was studied by NMR exchange lifetime measurement. At 297 K, k(on) ≈ 1.5 × 10(6) M(-1) s(-1) and k(off) = 45 s(-1), which represent the fastest Xe association and dissociation rates measured for a high-affinity, water-soluble xenon host molecule near rt. NMR line width measurements provided similar exchange rates at rt, which we assign to solvent-Xe exchange in TAAC. At 320 K, k(off) was estimated to be 1.1 × 10(3) s(-1). In Hyper-CEST NMR experiments, the rate of (129)Xe depolarization achieved by 14 pM TAAC in the presence of radio frequency (RF) pulses was calculated to be 0.17 μM·s(-1). On a per cryptophane basis, this equates to 1.2 × 10(4)(129)Xe atoms s(-1) (or 4.6 × 10(4) Xe atoms s(-1), all Xe isotopes), which is more than an order of magnitude faster than k(off), the directly measurable Xe-TAAC exchange rate. This compels us to consider multiple Xe exchange processes for cryptophane-mediated bulk (129)Xe depolarization, which provide at least 10(7)-fold sensitivity enhancements over directly detected hyperpolarized (129)Xe NMR signals.