Abstract: Per- and polyfluoroalkyl substances (PFASs) with persistence, bioaccumulation, and toxicity (PBT) properties have gained attention worldwide because of their potential environmental risks and adverse health effects. Regulation of PFASs remains a big concern for society. Based on the knowledge that C-F is the strongest single bond in organic chemistry, PFASs are considered as high persistent substances by some scientists. Therefore, it is recommended that PFASs be managed as a highly persistent category and that all ‘nonessential’ uses of these chemicals should be phased out. In view of their wide application in various fields, involving huge socio-economic impacts, accelerating the phase-out of PFASs is bound to have a huge impact on society and economy. It is therefore a long way to go in reaching consensus on PFASs management. As a result, phasing out PFASs requires a lengthy transition period. Currently, meaningful actions are needed to minimize the potential exposure risk of PFASs while meeting their social needs. In fact, there are approximately 5000 PFASs available on the global market. Studies indicate that the transformation behaviors of PFASs happen under different conditions, which result in various kinds of new emerging PFASs in natural environment and biota. There are limited data on the PBT properties of these new PFASs. Actually, some new PFASs are environmentally friendly themselves, but they can degrade to highly toxic and persistent PFASs such as PFOS, PFOA and PFHxS. These transformation products thereby become indirect sources of traditional PFASs in the environment, which would eventually lead to constant human exposure to these chemicals. Thus, it is very important to study the transformation of PFASs. Transformational studies can help identify transformational products with lower persistence and toxicity, which will provide valuable insights into the design of safer fluorinated alternatives. Here, for the first time, we propose that strengthening the study on the transformation of PFASs is an important strategy for classifying and managing fluorinated alternatives, and this will provide technical framework and support for the regulation of fluorinated alternatives. Furthermore, we make these proposals on the way forward for investigating transformational process of PFASs. Firstly, nontargeted and high-resolution mass spectrometry technologies must be continually developed, as these investigation methods are able to implement high throughput analysis of transformation products by assembling formulas and possible structures from molecular precursor and fragment data of existing PFASs. Secondly, the transmission, accumulation, metabolism, and elimination behaviors of PFASs in different matrices should be of high concern. In this regard, a combination of multi-omics, high-throughput toxicity testing, theory calculation, and machine learning is recommended to explor the potential mechanisms, and the essential factors affecting the process. Through this, the transformation products with PBT properties can be ascertained, prioritized, and managed. Lastly, biological networks elaborating the relationship between PFASs transformation products and adverse health effects should be established. The transformation products of PFASs may eventually pose adverse public health risks, which suggests that mapping a systematic transformation network would be beneficial to the classified management of fluorinated alternatives. This is challenging because of their diverse structures and huge numbers, however, the accomplishment of the first two proposals above will facilitate this process.