Most embryo culture media are still supplemented with proteins rather than with nonprotein macromolecules or recombinant protein products. HSA is probably the most common supplement followed by globulin-enriched preparations. Serum supplementation and Co-Culture of embryos belong to the past. Defined nonprotein or recombinant protein supplements are becoming a viable alternative during gamete and embryo manipulation procedures. Biological protein supplements are still preferred for any extended period of embryo culture. Understanding the goals and purpose of supplemented macromolecules in embryo culture media during each step of the laboratory IVF process should assist us in choosing the safest and most consistent macromolecule for each step, but also selecting a product that has the capability of delivering the best clinical outcome. Each batch of biological protein supplement is unique, even if supplied by the same manufacturer. Each lot of protein supplement typically contains many lot-specific, potentially harmful, and unintended hormone and protein contaminants. Macromolecular embryo culture medium supplements should be identified as one of the highest risk factors in an IVF laboratory that may contribute towards clinical compromise. All efforts should be made to use a proven batch of supplement for as long as the expiration date will allow. The beneficial effect of more complex protein supplements is evident after the activation of the embryonic genome and probably due to the presence of growth factors. Lower live-birth rates due to suboptimum protein supplementation may be a direct result of the preferential loss of female embryos. When deciding on a culture system, thought should be given specifically to the interaction between the culture medium and the macromolecular supplement. Ready-to-use pre-supplemented culture media may be advisable over a more complex product if a comprehensive macromolecular quality management program is not feasible. However, the question remains as to whether the increasing simplification of embryo culture media supplements is ready for large-scale clinical use.