The components of cryopreservation solutions can be classified into three general classes: (1) carrier solutes, which are the non-penetrating osmolytes, pH buffers, and nutritive ingredients that support viability of cells at hypothermic temperatures; (2) bulk cryoprotectants, which are ingredients (either membrane-penetrating or non-penetrating) typically added at multi-percent concentrations that reduce availability of bulk liquid water for ice formation by hydrogen bonding and dilution; (3) solutes that specifically interact with ice nucleating particles or ice crystals to inhibit or modify the growth of ice, and which are typically effective at very low concentrations. Class 3 solutes may exhibit ice nucleation inhibition (INI), ice growth inhibition (IGI), and/or ice recrystallization inhibition (IRI). Such solutes are valuable additives in vitrification solutions because they can replace much larger concentrations of more toxic bulk cryoprotectants while achieving similar suppression of ice formation. Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) are the prototypical examples of class 3 solutes. Fahy proposed in 1995 that synthetic analogs of AFPs would be useful additives for vitrification solutions, especially if lower molecular weights conveyed higher mobility in the high viscosity of vitrification solutions at low temperature. Subsequently, low molecular weight versions of the polymers polyvinyl alcohol (PVA) and polyglycerol (PGL) were found to show efficacy for numerous applications as “ice blockers” in vitrification solutions. PGL is apparently a specific INI against ice-nucleating protein contaminants, while PVA exhibits general INI, IGI, and IRI activity. Low molecular weight PVA and PGL are backbones of the advanced M22 and VM3 vitrification solutions. There are other INIs in the literature, such as flavonol glycosides, and new families of synthetic IRI inhibitors that may also be useful for cryopreservation. Even in circumstances in which ice nucleation cannot be avoided during vitrification, injury might be prevented if IRIs can keep ice crystals sufficiently small during warming. There is, however, a deficiency of small synthetic molecules with the same broad anti-ice activity as PVA. Small molecules are preferred because of greater mobility and decreased contribution to solution viscosity (low viscosity being important for perfusion cryoprotection of organs). Even though syndiotactic PVA oligomers have stable conformations with excellent alignment of hydroxyls for bonding to the basal plane of ice, a custom synthesized four “mer” PVA oligomer (1,3,5,7-heptanetetrol) was found to be inactive as an ice blocker in our laboratory. Subsequent structure-activity studies by Gibson’s group showed that PVA IRI activity ceases somewhere between 10 and 19 mers (400–800 MW). Evidently if a molecule is small, molecular models showing structural matching to an ice crystal surface, such as is seen with cyclohexanediols and triols, are not sufficient to establish identity as an ice blocker. Nor are empirical results at concentrations high enough ( ∼ > 1 mg/g) to enable bulk cryoprotective effects. Until good models and understanding of how known synthetic ice blockers or IRIs work are developed, prospects for finding or making new ones are limited. Protein-based compounds are understood better, but have obstacles of cost, stability in cryoprotectant solutions, and possible antigenicity.