The blood–brain barrier (BBB) expresses a high abundance of transporters, particularly P‐glycoprotein (P‐gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P‐gp at the BBB in drug discovery and development. We highlight the differences in P‐gp expression and protein levels across species but the limited observations of species‐specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P‐gp for several neurological disorders and ageing and exemplify several disease‐specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS‐related drug‐drug interactions due to the inhibition or induction of P‐gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P‐gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.