Macromolecular therapeutics, in particular, many biologics, is the most advancing category of drugs over conventional chemical drugs. The potency and specificity of the biologics for curing certain disease made them to be a leading compound in the pharmaceutical industry. However, due to their intrinsic nature, including high molecular weight, hydrophilicity and instability, they are difficult to be administered via non-invasive route. This is a major quest especially in biologics, as they are frequently used clinically for chronic disorders, which requires long-term administration. Therefore, many efforts have been made to develop formulation for non-invasive administration, in attempt to improve patient compliance and convenience. In this review, strategies for non-invasive delivery, in particular, oral, pulmonary and nasal delivery, that are recently adopted for delivery of biologics are discussed. Insulin, calcitonin and heparin were mainly focused for the discussion as they could represent protein, polypeptide and polysaccharide drugs, respectively. Many recent attempts for non-invasive delivery of biologics are compared to provide an insight of developing successful delivery system.