Some receptors remain unoccupied even when an agonist produces a maximal response. Such empty ones are called spare receptors. In presence of spare receptors the maximum effect of an agonist drug is achieved with fewer than 100% of the receptors being occupied. To determine the presence of spare receptors, scientists often compare the concentration of the drug needed to produce 50% of the maximum effect (EC₅₀) with the concentration of the drug needed to occupy 50% of the receptors (K_d). If the EC₅₀ is smaller than the K_d, spare receptors are said to be present.

Spare receptors act as functional reserves and allow cells to economically use endogenous agonists such as hormones and neurotransmitters.

The presence of spare receptors is indicated by two mechanisms that amplify signal duration and intensity.

• In some pathways, a single agonist-receptor complex activates multiple downstream effector proteins. In this case, receptor numbers surpass the available effector molecules as all receptors need not be occupied to produce a maximal response.
• In addition, even after the agonist-receptor complex dissociates, the activated effector molecules keep activating target proteins. Due to this reason, only a fraction of receptors is enough to produce the desired effect, and the rest remain unused.

The availability of these surplus receptors increases the cell's sensitivity toward the agonist. Cells are sensitive to a small change in insulin levels because 99% of them are spare. This indicates that only a small fraction of activated insulin receptors are enough to allow glucose uptake and meet the energy requirement of cells.

These spare receptors make a small amount of agonist more effective. At the same time, these receptors indicate that a higher concentration of antagonist is needed to diminish the agonist's effect. In the example of insulin receptors, even in the presence of insulin, 99% of receptors are unoccupied. To counteract insulin's response, the antagonist also needs to occupy these 99% spare receptors, indicating the need for higher antagonist concentration compared to the agonist. In contrast, the heart has only 5% to 10% of spare β-adrenoceptors, indicating that a low amount of β-blockers is sufficient to revive a failing heart.