Batteries are often not terribly fond of being wired directly in parallel, since any mismatch in the open-circuit voltage will result in the higher-voltage battery feeding current into the weaker one. If one is using rechargeable batteries and the charge states are sufficiently close, this may simply result in the batteries trying to equalize each other. When using primary-cell batteries, however, or if the charge states are not particularly close, this current flow may be detrimental to both batteries.
Wiring batteries in series is often safer, provided that current shuts off before any battery's voltage drops below its minimum safe level. For primary-cell batteries, the minimum safe level is roughly zero volts (the concern not being "damage" to a dead and useless battery, but rather the possibility that a back-driving primary cell battery may dump harmful chemicals on nearby circuitry). For rechargeable-cell batteries, the minimum safe voltage is much higher (draining batteries below that point may greatly accelerate wear).
Any differences in the efficiencies of step-up versus step-down conversion are apt to be minor compared with issues resulting from series or parallel battery connections.