Subcutaneous (SC) injection is currently the most common route of self-administering biopharmaceuticals such as proteins and peptides. While pharmaceutical scientists have acquired great skill in identifying formulations for these proteins and peptides with multi-year shelf life stability, the SC injection of these formulations can result in inconsistent or particularly low bioavailability outcomes. We hypothesise that upon injection, the chemical, physical and physiological properties of the subcutaneous tissue may play a crucial role in determining the therapeutic outcomes of SC injected biopharmaceuticals. We contend that physical and chemical stresses placed upon the injected protein or peptide as it transitions from the non-physiological environment of its formulation to the homeostatic conditions of the SC tissue can affect its fate following injection, and that by taking this environment into account when formulating, more precisely controlled release of SC injected biopharmaceuticals could be achieved. In this mini-review we describe how events that occur to an injected protein or peptide during this post-injection transition period could affect the diffusion of bioactive material to blood capillaries and lymphatic vessels. With this in mind, we have reviewed the chemical, physical and physiological attributes of the SC tissue and collated studies on how these properties are known to affect protein stability and diffusional properties. Finally, examples where the understanding of the properties of the SC tissue when formulating for SC injected biopharmaceuticals has improved the predictability of drug delivery via the SC route are discussed, with the need for novel tools for rational and informed formulation development highlighted.