Supramolecular calix[4]arene conjugate (L) has been developed as a sensitive and selective sensor for Zn 2+ in HEPES buffer among the 12 metal ion by using fluorescence, absorption and ESI MS and also by visual fluorescent color. The structural, electronic, and emission properties of the calix[4]arene conjugates L and its zinc complex, [ZnL], have been demonstrated using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The TDDFT calculations reveal the switch on fluorescence behavior of L is mainly due to the utilization of the lone pair of electrons on imine moiety by the Zn 2+. The resultant fluorescent complex, [ZnL], has been used as a secondary sensing chemo-ensemble for the detection of -SH containing molecules by removing Zn 2+ from [ZnL] and forming {Cys/DTT·Zn} adducts as equivalent to those present in metallothioneins. The displacement followed by the release of the coordinated zinc from its Cys/DTT complex by heavy metal ion (viz. Cd 2+ and Hg 2+), as in the metal detoxification process or by ROS (such as H 2O 2) as in the oxidative stress, has been well demonstrated using the conjugate L through the fluorescence intensity retrieval wherein the fluorescence intensity is the same as that observed with [ZnL], which in turn mimics the zinc sensing element (MTF) in biology (Figure presented). © 2011 American Chemical Society.