Sulfur(II)-containing polymers (polysulfides) combine flexible synthetic and processing techniques with a unique responsiveness to oxidants. Here, the polysulfide oxidative sensitivity is put into the biological context of the development of new anti-inflammatory therapies - the development of new anti-inflammatory methodologies, adopted interactions and the minimisation of foreign-body reactions -through the review of 50 years of research on polysulfide synthetic methodologies. Attention is paid to the identification of the most flexible and robust preparative techniques.