Infants are therapeutic orphans. Many drugs used in infants are used "off-label", increasing the risk of drug toxicity and suboptimal efficacy in this vulnerable population. This knowledge gap in clinical pharmacology is partly attributed to challenges associated with conducting clinical trials in infants. Consequently, there is a need for novel and efficient study designs more suited to this population. Available literature describing the use of minimal-risk approaches to characterize the pharmacokinetics (PK) of drugs in infants was critically reviewed. Population PK approach with sparse sampling was found to be well established. Other, more recent alternatives, like dried blood spots sampling, opportunistic design, and the use of non-blood matrices are promising strategies with an increasing number of applications in infants. Physiologically based pharmacokinetic modeling provides valuable insight in drug disposition but still needs more prospective validation. Increasing experience with these methods provides understanding of their strengths and limitations and will help improve the design of future PK studies in infants.