Polymers have played an enabling role in the field of long-acting injectables (LAIs). Progress in polymer chemistry and our ability to successful apply these materials has advanced significantly over the last century. The advent of the first bioresorbable sutures from polyglycolic acid in 1970 (Bender and Brouwer, Arch Chir Neerl 27(1):53–61, 1975) and first lactide glycolide copolymer microsphere product in 1986 heralded a new field of degradable polymer applications in medicine. With the first LAI, these polymers unlocked a new drug delivery paradigm and continue to offer significant improvements in patient outcomes. This chapter explores both natural and synthetic polymers including well-established and some more novel technologies being evaluated in this space. Natural polymers (including polysaccharides, proteins, and microbial derived polymers) and synthetic polymers (including polyanhydrides, polyorthoesters, and polyesters) are reviewed. Given their importance to the field as the gold standard polymeric material used in these depots, aliphatic polyesters from lactide glycolide chemistries are reviewed in significant detail including their history, commercial uses, routes of synthesis, regulatory status, appropriate characterization, and quality control. We also present theoretical adjustments that can be made to these polymers to effectively tune and control drug release. Finally, we discuss some current challenges and unmet needs and future perspective.