Piezo1 is a mechanosensitive ion channel noted for its exceptional complexity and involvement in force sensing in a broad range of tissues, including cartilage, bone, skin, blood vessels and lymph nodes. While cell-specific splice variants have been reported in the closely related Piezo2 channel, and various membrane proteins and lipids have been demonstrated to modulate the mechanotransduction process, it is less clear how Piezo1 attunes itself to tissue microenvironments with greatly divergent force profiles. Here, we describe chimeric cpGFP/Piezo1 probes that selectively respond to shear stress with a strong and irreversible increase in fluorescence intensity. Probe sensitivity is correlated with the presence an actin cytoskeleton, the inhibition of which dampens but does not eliminate the signal. The reporters retain functional pores and allow cation entry in response to the Piezo1 agonist Yoda1, as well as poking with a glass probe and exposure to a hypotonic environment, but these stimuli do not trigger a fluorescent response. Similarly, no shear response is provided by cpGFP inserted into other regions of Piezo1, as well as non-mechanosensitive reporters (Lck-cpGFP and the voltage-sensitive reporter ASAP1). Evolutionary analysis of Piezo1 sequences show that different clusters of conserved and co-mutating residues exist in the blade region, suggesting that multiple allosteric pathways may be responsible for conveying different types of mechanical stress to the pore. We propose that other sets of Piezo1 insertions can be used to determine the function of these clusters.