Recently, new long-acting formulations of racemic methylphenidate (MPH: Ritalin LA, Metadate CD and Concerta) and amphetamine (AMP: Adderall XR) were developed and are now approved by the Food and Drug Administration (FDA). In addition, dexmethylphenidate (Focalin), the pharmacologically active d-threo enantiomer of MPH, also was approved by the FDA. In the initial phases of development, prototypes of these five new formulations were evaluated using the University of California, Irvine (UCI) Laboratory School Protocol (LSP), in which surrogate measures of efficacy are collected in highly controlled settings rather than clinical measures of effectiveness in the less-controlled, natural environments of home or school. The LSP studies were followed by large effectiveness and safety studies required for gaining FDA approval. These initial efficacy and side effect studies in the LSP provided missing information about the basic pharmacokinetic (PK) and pharmacodynamic (PD) properties of MPH and AMP and produced some new discoveries (i.e., acute tolerance) that were used to help design the final products. The final once-a-day formulations used different drug delivery systems to achieve long-acting efficacy (Ritalin LA, Metadate CD, Concerta, Adderall XR). All four drug delivery systems were based on two processes: first, a bolus delivery (BD) process to achieve rapid onset of efficacy (mg), and second, a controlled delivery (CD) process to achieve rates of delivery (mg/hr) or a delayed bolus (mg) to maintain efficacy. A theoretical approach was used to compare and contrast the new once-a day formulations of MPH by selecting total daily doses (mg/d) that would equate drug delivery by the first process (mg of the initial bolus) and the second process (mg/hr over specified time period). In addition to efficacy, applications of the LSP to measure common side effects related to eating and sleeping were described and discussed.